Water-soluble phenylpyridazine derivative and medicine containing the same

ABSTRACT

A phenylpyridazine derivative represented by the formula (1): 
                         
Wherein, R1, R2, R3, X, Y, Z and n have the same meaning as defined in the specification; or a salt thereof, or a medicine containing the compound. The present invention provides water-soluble phenylpyridazine derivatives and medicines containing them, which have excellent inhibitory activity against interleukin-β production, high water solubility and high oral absorbability.

TECHNICAL FIELD

This invention relates to water-soluble phenylpyridazine derivatives,which exhibit excellent inhibitory activity against interleukin-1βproduction, have high water solubility and oral absorbability, and areuseful for the prevention and treatment of immune system diseases,inflammatory diseases, and ischemic diseases, for example, and also tomedicines containing them as active ingredients.

BACKGROUND ART

In many diseases, for example, rheumatism, arthritis, osteoporosis,inflammatory colitis, immune deficiency syndrome, ichorrhemia,hepatitis, nephritis, ischemic diseases, insulin-dependent diabetesmellitus, arterial sclerosis, Parkinson's disease, Alzheimer's disease,and leukemia, an increased production of interleukin-1β, which is aninflammatory cytokine, is observed. This interleukin-1β serves to inducesynthesis of an enzyme which is considered to take part ininflammation—like collagenase and PLA2- and, when intra-articularlyinjected to animals, causes multiarticular damage highly resemblingrheumatoid arthritis. In a healthy body, on the other hand, the activityof interleukin-1β is controlled by interleukin-1 receptor, solubleinterleukin-1 receptor and interleukin-1 receptor antagonist.

From research conducted using recombinant bioactivity-inhibitingsubstances, anti-interleukin-1β antibodies and anti-receptor antibodiesagainst various disease models and also from research performed usingknockout mice, interleukin-1β has been found to play an important rolein the body, leading to an increasing potential of substances havinginterleukin-1β inhibitory activity as therapeutics for such diseases.

For example, immunosuppressors and steroids, which are used for thetreatment of rheumatism among these many diseases, have been reported toinhibit production of interleukin-1β. Among compounds currently underdevelopment, KE298, a benzoylpropionic acid derivative [The JapaneseSociety of Inflammation (11th), 1990], for example, has been reported toalso exhibit inhibitory activity against interleukin-1β productionalthough it is an immunoregulator. Inhibitory activity againstinterleukin-1β production is also observed in a group of compounds whichare called “COX-2 selective inhibitors”, for example, nimesulide as aphenoxysulfonanilide derivative (DE Publication No. 2333643), T-614 as aphenoxybenzopyran derivative (U.S. Pat. No. 4,954,518), and tenidap(oxyindole derivative) as a dual inhibitor (COX-1/5-LO).

However, interleukin-1β production inhibitory activity is not theprimary action or effect of any of these compounds so that theinhibitory activity against interleukin-1β production is less than theprimary action thereof.

More recently, increased synthetic research has been conductedemphasizing inhibitory activity against interleukin-1β production.Production inhibitors can be classified into a group of compounds whichinhibit the transfer process and an inflammatory signal to a cellnucleus, the transcription or translation stage, and another group ofcompounds which inhibit the enzyme ICE that functions in the processingof a precursor of interleukin-1β. Known examples of compounds presumedto have the former action include SB203580 [JP-A-1995-503017], FR167653(Eur. J. Pharm., 327, 169–175, 1997), E-5090 (EP Patent Publication No.376288), CGP47969A (Gastroenterology, 109, 812–818, 1995), hydroxyindolederivatives (Eur. J. Med. Chem. 31, 187–198, 1996), and triarylpyrrolederivatives (WO 9705878), while known examples of compounds presumed tohave the latter action include VE-13,045 which is a peptide compound(Cytokine, 8(5), 377–386, 1996).

None of these compounds, however, exhibit sufficient inhibitory activityagainst interleukin-1β production.

On the other hand, it is known that 5,6-diphenyl-pyridazine derivativesexhibit analgesic and anti-inflammatory action (Eur. J. Med. Chem., 14,53–60, 1979). Further, 6-phenylpyridazinones have been reported to beuseful as cardiotovics (U.S. Pat. No. 4,404,203). Nothing has beenreported, however, with respect to inhibitory activity of thesepyridazine compounds against interleukin-1β production.

The present inventors previously reported in WO 99/44995 that highinhibitory activity against interleukin-1β production was observed onphenylpyridazine derivatives. Recently, certain phenylpyridazinederivatives having inhibitory activity against interleukin-1β productionhave been reported (JP 7-69894 A, WO 98/41511, WO 99/10331, WO 99/10332,WO99/25697, WO00/50408). These reported compounds, however, aredifferent in chemical structure from the compounds of the presentinvention.

DISCLOSURE OF THE INVENTION

The compounds disclosed in WO 99/44995 exhibit strong inhibitoryactivity against interleukin-1β production. However, the watersolubility of these compounds is so low that formulating them intopharmaceutical preparations, such as tablets, required furtherinvestigations. In the course of a further investigation, the presentinventors discovered that the introduction of a substituted orunsubstituted aminoalkyl group to the 4-position of6-phenylpyridazin-3-one affords a compound useful as a preventive ortherapeutic for immune system diseases, inflammatory diseases, andischemic diseases, for example, due to its significantly improved watersolubility, good oral absorbability and excellent inhibitory activityagainst interleukin-1β production, leading to the completion of thepresent invention.

Thus, in one aspect of the present invention, there is provided aphenylpyridazine derivative represented by the formula (1):

wherein:

R¹ is optionally substituted alkyl, or optionally substituted alkenyl;

R² and R³ each independently represents hydrogen or alkyl, hydroxyalkyl,dihydroxyalkyl or alkynyl, or R² and R³ are fused together with theadjacent nitrogen atom to form an optionally substituted,nitrogen-containing saturated heterocyclic group;

X, Y and Z each independently represents hydrogen, halogen, optionallysubstituted alkyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl, oroptionally substituted aryl; and

n stands for a number of from 1 to 5;

with the proviso that R² and R³ are not hydrogen atoms or the same C₁–C₃alkyl groups at the same time when R¹ is a benzyl group or a C₁–C₃ alkylgroup; or a salt thereof.

In another aspect of the present invention, there is also provided amedicine comprising the phenylpyridazine derivative or the salt thereofas an active ingredient.

In a further aspect of the present invention, there is also provided apharmaceutical composition comprising the phenylpyridazine derivative(1) or the salt thereof and a pharmacologically acceptable carrier.

In a still further aspect of the present invention, there is alsoprovided use of the phenylpyridazine derivative (1) or the salt thereoffor the production of a medicine.

In a yet further aspect of the present invention, there is also provideda method for treating a disease caused by increased production ofinterleukin-1β production, which comprises administering thephenylpyridazine derivative (1) or the salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphic representation of the oral absorbability of acompound according to the present invention (Example 83) and acomparative compound 3;

FIG. 2 is graphic representations of the oral absorbability of acompound according to the present invention (Example 23);

FIG. 3 is graphic representations of the oral absorbability of acompound according to the present invention (Example 25);

FIG. 4 is graphic representations of the oral absorbability of a furthercompound according to the present invention (Example 143);

FIG. 5 is graphic representations of the oral absorbability of compoundsaccording to the present invention (Example 245 and Example 246); and

FIG. 6 is graphic representations of the oral absorbability of compoundsaccording to the present invention (Example 193, Example 247, Example248 and Example 249).

BEST MODES FOR CARRYING OUT THE INVENTION

In the above formula (1), the alkyl moieties in the alkyl, hydroxyalkyl,dihydroxyalkyl, alkoxy, alkylthio, alkylsulfinyl and alkylsulfonylrepresent those having 1 to 12 carbon atoms, more preferably 1 to 7carbon atoms. These alkyl moieties include linear, branched, cyclic aswell as alkyl groups having cyclic structures, for example, methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl,cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

In the above formula (1), the alkyl represented by R¹ has preferably 1to 12 carbon atoms, more preferably 1 to 7 carbon atoms, notably 4 to 7carbon atoms. Illustrative of such alkyl groups are linear, branched,cyclic as well as alkyl groups having cyclic structures. Preferredexamples include methyl, ethyl, propyl, isobutyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl,cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl, with methyl,ethyl, isobutyl, cyclopropylmethyl and cyclopentylmethyl beingparticularly preferred.

The alkenyl represented by R¹ preferably has 2 to 12 carbon atoms, with2 to 7 carbon atoms being particularly preferred. Illustrative of suchalkenyl groups are linear and branched alkenyl groups, for example,vinyl, propenyl, butenyl and pentenyl.

Illustrative of group(s) which the alkyl or alkenyl group represented byR¹ may contain as substituent (s) are optionally substituted aryl groupsand optionally substituted heteroaryl groups. Examples of the arylgroups include aryl groups having 6 to 14 carbon atoms, for example,phenyl and naphthyl, with phenyl being particularly preferred. Examplesof the heteroaryl groups, on the other hand, include 5- or 6-memberedcyclic heteroaryl groups having 1 to 3 nitrogen atoms, for example,pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl andpyridazinyl, with pyridyl being particularly preferred.

These aryl or heteroaryl groups may contain 1 to 3 substituents such ashalogen atoms, alkyl groups or alkoxy groups. Examples of the halogenatoms include fluorine, chlorine, bromine and iodine, with fluorine andchlorine being particularly preferred. These alkyl and alkoxy groupspreferably have 1 to 12 carbon atoms, with 1 to 7 carbon atoms beingparticularly preferred.

The alkyl, hydroxyalkyl and dihydroxyalkyl represented by R² and R³preferably have 1 to 12 carbon atoms, with 1 to 7 carbon atoms beingparticularly preferred. These groups may preferably be linear orbranched. Specific examples include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, hydroxyethyl, hydroxypropyl, hydroxybutyl,dihydroxypropyl and dihydroxybutyl.

The alkynyls represented by R² and R³ preferably have 3 to 12 carbonatoms, with 3 to 7 carbon atoms being particularly preferred.Illustrative is propargyl (2-propynyl).

Illustrative of the nitrogen-containing, saturated heterocyclic groupwhich may be formed as a result of fusion of R² and R³ with the adjacentnitrogen atom are 5- to 7-membered saturated heterocyclic groups, forexample, pyrrolidinyl, piperidino, piperazinyl, homopiperazinyl andmorpholino, with pyrrolidinyl, piperazinyl, piperidino and morpholinobeing particularly preferred.

Illustrative of group(s) which these heterocyclic groups may contain assubstituent (s) are halogen atoms, alkyl groups, alkoxycarbonyl groupsand aralkyl groups. Examples of the halogen atoms include fluorine,chlorine, bromine and iodine. The alkyl groups can contain 1 to 12carbon atoms, preferably 1 to 7 carbon atoms. Illustrative of thealkoxycarbonyl groups are C₁–C₁₂ alkyloxycarbonyl groups, with C₁–C₇alkyloxycarbonyl groups being preferred. Illustrative of the aralkylgroups are phenyl (C₁–C₇ alkyl) groups, with benzyl being particularlypreferred.

Illustrative of the halogens represented by X, Y and Z are fluorine,chlorine, bromine, and iodine. The alkyl groups can contain 1 to 12carbon atoms, with 1 to 7 carbon atoms being particularly preferred.Among these alkyl groups, linear or branched ones are particularlypreferred. Illustrative of group(s) which the alkyl group may contain assubstituent(s) are halogen atoms and alkoxy groups. The alkoxy,alkylthio, alkylsulfinyl and alkylsulfonyl groups can contain 1 to 12carbon atoms, with 1 to 7 carbon atoms being particularly preferred.Among these alkoxy, alkylthio, alkylsulfinyl and alkylsulfonyl groups,linear or branched ones are particularly preferred. Specific examplesinclude methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylthio,ethylthio, propylthio, isopropylthio, butylthio, methylsulfinyl,ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl,methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, andbutylsulfonyl. Illustrative of the aryl are aryl groups having 6 to 14carbon atoms, for example, phenyl and naphthyl, with phenyl beingparticularly preferred. Illustrative of group(s) which the aryl maycontain as substituent (s) are halogen atoms, alkyl groups, and alkoxygroups.

n stands for a number of from 1 to 5, with 1 to 3 being more preferred,and with 1 or 3 being particularly preferred.

When R¹ is a benzyl group or a C₁–C₃ alkyl group, R² and R³ are nothydrogen atoms or the same C₁–C₃ alkyl groups at the same time.

In the formula (1), particularly preferred as R¹ are isobutyl,cyclopropylmethyl, cyclopentylmethyl, cinnamyl, halogenocinnamyl,benzyl, halogenobenzyl, dihalogenobenzyl, (halogenophenyl)ethyl,(dihalogenophenyl)ethyl, (halogenophenyl)propyl, and(dihalogenophenyl)propy. Specifically, chlorobenzyl, dichlorobenzyl,fluorobenzyl, difluorobenzyl, (chlorophenyl)ethyl,(dichlorophenyl)ethyl, (fluorophenyl)ethyl, (difluorophenyl)ethyl,(chlorophenyl)propyl, (dichlorophenyl)propyl, (fluorophenyl) propyl and(difluorophenyl) propyl are preferred in particular. Preferred as R² andR³ are hydrogen, C₁₋₇ alkyl, C₁₋₇hydroxyalkyl, and propargyl. Preferredas the heterocyclic group formed by R² and R³ are piperazinyl,piperidino, pyrrolidinyl and morpholino, each of which may optionally besubstituted by one or more C₁₋₇ alkyl or benzyl groups. Preferred as Xare methyl, methoxy, methylthio, and halogens. Preferred as Y arehydrogen, methyl and halogens. Preferred as Z is hydrogen. Preferred asn are 1 and 3.

In the present invention, still more preferred are compounds of theformula (1) in which R¹ is a group selected from halogenobenzyl,dihalogenobenzyl, (halogenophenyl) ethyl, (dihalogenophenyl)ethyl,(halogenophenyl)propyl or (dihalogenophenyl)propyl; R²(R³)N— is a groupselected from amino, dimethylamino, piperazinyl or N-methylpiperazinyl;X is halogen or methoxy; Y is methyl or halogen; Z is hydrogen; and nstands for 1 or 3.

Particularly preferred are compounds of the formula (1) in which R¹ is agroup selected from chlorobenzyl, dichlorobenzyl, fluorobenzyl,difluorobenzyl, (chlorophenyl)ethyl, (dichlorophenyl)ethyl,(chlrorophenyl)propyl or (dichlorophenyl)propyl; R²(R³)N— is a groupselected from amino, dimethylamino, piperazinyl or N-methylpiperazinyl;X is halogen or methoxy; Y is methyl or halogen; Z is hydrogen; and nstands for 1 or 3.

Among these, the following compounds are preferred:

-   4-dimethylaminomethyl-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one,-   2-cyclopropylmethyl-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,-   2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-benzyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,-   4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,-   4-aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,-   4-dimethylaminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one,-   4-diethylaminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one,-   4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one,-   6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one,-   4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one,-   2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one,-   4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one,-   2-cyclopropylmethyl-4-dimethylaminomethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one,-   2-isobutyl-6-[4-(methylthio)phenyl]-4-propargylaminomethyl-2H-pyridazin-3-one,-   4-dimethylaminomethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one,-   2-(4-chlorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,-   2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-cyclopentylmethyl-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,-   2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,-   4-aminomethyl-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,-   2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   4-dimethylaminomethyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,-   2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,-   4-aminomethyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,-   4-aminomethyl-2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,-   2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-(3,4-difluorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,-   6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-one,-   4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-one,-   6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,-   4-aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-one,-   2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-[4-(2-hydroxyethyl)-1-piperazinyl]methyl-2H-pyridazin-3-one,-   2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(4-methyl-1-piperazinyl)propyl]-2H-pyridazin-3-one,-   2-cyclopropylmethyl-4-(3-dimethylaminopropyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,-   2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one,    and-   4-(3-aminopropyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one.

Further, the following compounds are especially preferred:

-   2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-[3-(2-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-[3-(3-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-[3-(4-methyl-1-piperazinyl)propyl]-2H-pyridazin-3-one,-   4-(3-aminopropyl)-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one,-   2-[2-(2-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,-   4-aminomethyl-2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one,-   2-[3-(2,6-dichlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-(3,4-difluorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   4-aminomethyl-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one,-   2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxylphenyl)-4-[3-(4-methyl-1-piperazinyl)propyl]-2H-pyridazin-3-one,-   2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxylphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one,-   2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one-   2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one-   4-aminomethyl-2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxylphenyl)-2H-pyridazin-3-one,-   4-aminomethyl-2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxylphenyl)-2H-pyridazin-3-one,-   2-cyclopropylmethyl-6-(3-fluoro-4-methoxylphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one,-   4-(3-aminopropyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxylphenyl)-2H-pyridazin-3-one,-   2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxylphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-(3,4-difluorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxylphenyl)-2H-pyridazin-3-one,-   2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxylphenyl)-4-[4-(2-hydroxyethyl)-1-piperazinyl]methyl-2H-pyridazin-3-one,-   4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxylphenyl)-2H-pyridazin-3-one,-   4-aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxylphenyl)-2H-pyridazin-3-one,    and-   2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one.

In particular, the following compounds are preferred:

-   2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   4-(3-aminopropyl)-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one,-   2-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-cyclopropylmethyl-6-(3-fluoro-4-methoxylphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one,-   4-(3-aminopropyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxylphenyl)-2H-pyridazin-3-one,-   2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxylphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-(3,4-difluorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxylphenyl)-2H-pyridazin-3-one,-   2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxylphenyl)-4-[4-(2-hydroxyethyl)-1-piperazinyl]methyl-2H-pyridazin-3-one,-   4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxylphenyl)-2H-pyridazin-3-one,-   4-aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxylphenyl)-2H-pyridazin-3-one,    and-   2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one.

Specifically, the following compounds are preferred from the standpointof water solubility and oral absorbability:

-   2-(3,4-difluorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,-   2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,-   2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,    or-   2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-[4-(2-hydroxyethyl)-1-piperazinyl]methyl-2H-pyridazin-3-one;    or a salt thereof.

As the salt of the compound (1) of the present invention, an acidaddition salt is preferred. Examples of the acid addition salt includeinorganic acid salts, such as the hydrochloride, sulfate, nitrate andphosphate, and organic acid salts, such as the methanesulfonate,maleate, fumarate, citrate and oxalate.

Further, the compound according to the present invention may exist inthe form of solvates and a keto-enol tautomer. Such solvates andtautomer are encompassed by the present invention. Illustrative of thesolvates are those formed as a result of addition of solvents used uponproduction, for example, water and alcohols. No particular limitation isimposed on the solvents insofar as they do not adversely affect theinhibitory activity or the like of the compound according to the presentinvention against interleukin-1β production. As a solvate, the hydrateis preferred.

The phenylpyridazine compound (1) according to the present invention canbe prepared, for example, by the following preparation processes (a) to(d).

(a) Preparation Process of Compounds Having the Formula (1) in which n=1

wherein R⁴ represents alkyl, Hal represents halogen, Ms representsmethanesulfonyl, and R¹, R², R³, X, Y and Z have the same meanings asdescribed above.

A description will hereinafter be made about the individual reactionsteps.

In the steps from an acetophenone (2) to a compound (5), theacetophenone (2) and diethyl ketomalonate are heated under stirring toyield a compound (3). Hydrazine is caused to act on the compound tocarry out a ring-closing reaction, and the reaction product is thentreated with an alkali, for example, sodium hydroxide or the like toafford a compound (4). The compound (4) is next reacted with an alcoholsuch as methanol to give the compound (5).

R¹-Hal is reacted to the compound (5) in the presence of an alkali suchas potassium carbonate to provide a compound (6). The compound (6) ishydrolyzed into a compound (7). After ethyl chlorocarbonate is caused toact on the compound (7) to convert it into an acid anhydride, the acidanhydride is reduced with a reducing agent such as sodium borohydride toafford a compound (8). A reaction of methanesulfonyl chloride with thecompound (8) in the presence of a base such as triethylamine provides acompound (9), a key intermediate in this reaction scheme.

A reaction of a desired amine [R²(R³)NH] with the compound (9) yieldsthe target compound (1a). It is preferred to carry out this reaction,for example, in a polar solvent such as dimethylformamide in thepresence or absence of an alkali such as potassium carbonate.Incidentally, if an amino group is contained in the group R² or R³ inthe amine, a reaction may be carried out using a raw material protectedwith an appropriate protecting group, for example, an alkoxycarbonylgroup, followed by the removal of the protecting group.

To obtain a compound (1a) in which R² and R³ are hydrogen atoms,potassium phthalimide is reacted with the compound (9), and the reactionproduct is reacted further with hydrazine or the like.

A compound (1a) in which X, Y and/or Z is methylsulfinyl ormethylsulfonyl can be obtained by oxidizing a corresponding compound, inwhich X, Y and/or Z is methylthio, with a peracid, for example,perbenzoic acid. This methylsulfination or methylsulfonation may becarried out at the stage of the intermediate (9).

(b) Preparation Process of Compounds Having the Formula (1) in which n=3

wherein Hal, Ms, R¹, R², R³, X, Y and Z have the same meanings asdefined above.

According to the preparation process (b), a carbon tetrahalide such ascarbon tetrabromide is firstly reacted with the compound (8) in thepresence of triphenylphosphine to obtain a halide (10), with which amalonate is then reacted in the presence of sodium hydride to yield acompound (11). An acid such as trifluoroacetic acid is reacted with thecompound (11) to convert it into a dicarboxylic acid, followed byheating to yield a compound (12). Ethyl chlorocarbonate is caused to acton the compound (12) to convert it into an acid anhydride, which is thenreduced with a reducing agent such as sodium borohydride to yield acompound (13). Methanesulfonylchloride is reacted with the compound (13)in the presence of a base such as triethylamine to yield a compound(14), a key intermediate in the process according to the presentinvention.

A target compound (1b) can be obtained by reacting a corresponding amine(R²R³NH) with the compound (14). This reaction may preferably beconducted, for example, in the presence or absence of an alkali such aspotassium carbonate in a polar solvent such as dimethylformamide. Whenan amino group is contained in the group R² or R³ of the amine, areaction may be conducted using a raw material in which the amino grouphas been protected with an appropriate protecting group (for example, analkoxycarbonyl group), followed by deprotection of the protecting group.

To yield a compound (1b) in which R² and R³ are both hydrogen atoms, thecompound can be obtained by reacting potassium phthalimide with thecompound (14) and then reacting hydrazine or the like.

(c) Preparation Process of Compounds Having the Formula (1) in which n=2

wherein M represents a metal atom, and Hal, Ms, R¹, R², R³, X, Y and Zhave the same meanings as defined above.

According to the preparation process (c), a cyanide such as sodiumcyanide is reacted with a halide (10) to convert it into a nitrilederivative (15), which is then hydrolyzed to yield a compound (16). Fromthe compound (16), a target compound (1c) can be obtained via an alcoholderivative (17) and a mesyloxy derivative (18) by a similar procedure asin the preparation of compounds containing three methylene groups.

(d) Preparation Process of Compounds Having the Formula (1) in which n=4or 5

These compounds can be obtained by combining the synthesis processes (b)and (c).

The salt of the compound (1) according to the present invention can beobtained by causing an organic acid or inorganic acid to act in a mannerknown per se in the art.

The compound (1) according to the present invention can be isolated andpurified by subjecting it to purification procedures commonly employedin organic synthesis chemistry, for example, filtration, extraction,washing, drying, concentration, recrystallization, variouschromatographic procedures, and/or the like. Each intermediate can besubjected to the subsequent reaction without bothering to purify it. Thecompound (1) may be provided as a solvate with a solvent such as areaction solvent or recrystallization solvent, especially as thehydrate.

The compound (1) according to the present invention is excellent inwater solubility, is also good in oral absorbability and has inhibitoryactivity against interleukin-1β production, and therefore, is useful asa preventive or therapeutic for immune system diseases, inflammatorydiseases, ischemic diseases, osteoporosis, ichorrhemia and the like.Examples of ischemic diseases include ischemic heart diseases, ischemicencephalopathy, ischemic nephritis, and ischemic hepatitis.

The pharmaceutical composition of the present invention contains thecompound (1) or the salt thereof as an active ingredient. Using theactive ingredient alone or together with a pharmacologically acceptablecarrier such as a solubilizer, excipient, binder or extender, it can beformed into pharmaceutical preparation forms such as tablets, capsules,granules, powders, injections and suppositories. These pharmaceuticalpreparations can be produced by known methods. For example, oralpreparations can be produced by suitably formulating the compound (1) orthe salt in combination with solubilizers such as tragacanth gum,gumarabic, sucrose esters, lecithin, olive oil, soybean oil and PEG400;excipients such as starch, mannitol and lactose; binders such ascarboxymethylcellulose sodium and hydroxypropylcellulose; disintegratorssuch as crystalline cellulose and carboxymethylcellulose calcium;lubricants such as talc and magnesium stearate; anticaking agents suchas light anhydrous silicic acid. The pharmaceutical compositionaccording to the present invention is administered orally orparenterally.

The administered dosage of the pharmaceutical composition according tothe present invention varies depending on the body weight, age, sex,conditions and the like of each patient. In general, however, it ispreferred to administer to an adult in an amount of about 0.01 to 1,000mg, preferably 0.1 to 100 mg, of the present pharmaceutical compositionin terms of the compound (1) per day in 1 to 3 portions.

EXAMPLES

The present invention will now be further described by reference to thefollowing Examples. The Examples are provided solely for purposes ofillustration and are not intended to be limitative.

Example 1 Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one 1)Preparation of 4-(1-hydroxyethyl)-2-fluorotoluene

To an ice-cold solution of 3-fluoro-4-methylbenzaldehyde (50 mg, 0.36mmol) in THF (0.5 mL) was added dropwise a 0.93 M solution (0.47 mL) ofmethylmagnesium bromide (0.44 mmol) in THF. The temperature of thereaction mixture was allowed to rise back to room temperature, at whichthe reaction mixture was stirred for 1 hour. Then, 2 mol/L hydrochloricacid was added, and the mixture was extracted with ethyl acetate. Theextract was washed with brine and dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure to yield titlecompound as a pale yellow oil (55.8 mg, quantitative).

¹H NMR(400 MHz, CDCl₃)δ: 1.46(3H, d, J=6.4 Hz), 2.26(3H, d, J=1.8 Hz),4.85(1H, q, J=6.4 Hz), 6.99–7.06(2H, m), 7.14(1H, dd, J=7.8, 7.8 Hz).

2) Preparation of 3′-fluoro-4′-methylacetophenone

To a solution of 4-(1-hydroxyethyl)-2-fluorotoluene (55.8 mg, 0.36 mmol)in methylene chloride (1 mL) were added molecular sieve 4A (56.0 mg) andPCC 94.0 mg (0.43 mmol), and the mixture was stirred at room temperaturefor 1 hour. The reaction mixture was filtered through Celite, and thefiltrate was concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel [silica gel 5 g,hexane/ethyl acetate (10/1)] to yield the title compound as a paleyellow oil (47.5 mg, 86.0%).

¹H NMR(400 MHz, CDCl₃)δ: 2.32(3H, d, J=1.8 Hz), 2.56(3H, s), 7.26(1H,dd, J=7.6, 7.6 Hz), 7.56(1H, dd, J=1.6, 10.4 Hz), 7.62(1H, dd, J=1.6,7.8 Hz).

3) Preparation of ethyl2-ethoxycarbonyl-4-(3-fluoro-4-methylphenyl)-2-hydroxy-4-oxobutanoate

A mixture of 3′-fluoro-4′-methylacetophenone (4.92 g, 32.3 mmol) anddiethyl ketomalonate (6.19 g, 35.6 mmol) was stirred at 120° C. for 48hours. The temperature of the reaction mixture was allowed to drop backto room temperature, and the mixture was purified by columnchromatography on silica gel [silica gel 100 g, chloroform/ethyl acetate(10/1)] to yield the title compound as yellow crystals (8.41 g, 79.3%).

Melting point: 68.7–69.0° C. ¹H NMR(400 MHz, CDCl₃)δ: 1.30(6H, t, J=7.1Hz), 2.34(3H, s), 3.78(2H, s), 4.25(1H, s), 4.31(4H, q, J=7.1 Hz),7.29(1H, dd, J=7.6 Hz), 7.59(1H, d, J=10.2 Hz), 7.65(1H, dd, J=1.5, 7.8Hz). IR(KBr) cm⁻¹: 3485, 1740, 1684, 1253, 856, 577.

4) Preparation of4-carboxy-6-(3-fluoro-4-methylphenyl)-2H-pyridazin-3-one

To a solution of ethyl2-ethoxycarbonyl-4-(3-fluoro-4-methylphenyl)-2-hydroxy-4-oxobutanoate(8.41 g, 25.8 mmol) in isopropanol (100 mL) was added hydrazinemonohydrate (2.84 g, 56.8 mmol), and the mixture was heated understirring at 100° C. for 6 hours. Then, 2 mol/L sodium hydroxide wasadded, and the mixture was stirred further at the same temperature for 4hours. The reaction mixture was ice-cooled, and concentratedhydrochloric acid was added to acidify the system. The precipitate wascollected by filtration, thoroughly washed with water and dried to yieldthe title compound as a slightly yellow crystalline powder (5.67 g,87.7%).

Melting point: 281.3–282.0° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:2.28(3H, d, J=1.0 Hz), 7.41(1H, dd, J=8.1, 8.1 Hz), 7.67–7.73(2H, m),8.49(1H, s), 14.09(1H, br). IR(KBr) cm⁻¹: 1736, 1641, 1441, 1125, 926,806.

5) Preparation of6-(3-fluoro-4-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

To an ice-cold suspension of4-carboxy-6-(3-fluoro-4-methylphenyl)-2H-pyridazin-3-one (5.50 g, 22.2mmol) in methanol (100 mL) was added dropwise thionyl chloride (2.72 g,24.4 mmol), and the mixture was stirred at 80° C. for 8 hours. Thetemperature of the reaction mixture was allowed to drop back to roomtemperature, and the solvent was distilled off under reduced pressure.Water was added to the ice-cold residue. The precipitate was collectedby filtration, washed with water and dried to yield the title compoundas pale yellow fine-needles (5.43 g, 92.7%).

Melting point: 206.0–207.3° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.33(3H, d,J=1.7 Hz), 4.00(3H, s), 7.29(1H, dd, J=7.9, 7.9 Hz), 7.46–7.53(2H, m),8.32(1H, s), 11.61(1H, s). IR(KBr) cm⁻¹: 1715, 1671, 1266, 1177, 1091,812.

6) Preparation of6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one

To a solution of6-(3-fluoro-4-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one (5.28g, 20.0 mmol) in N,N-dimethylformamide (40 mL) were added potassiumcarbonate (5.53 g, 40.0 mmol) and isobutyl bromide (3.29 g, 24.0 mmol),and the mixture was stirred at 80° C. for 1 hour. The temperature of thereaction mixture was allowed to drop back to room temperature. Asaturated aqueous solution of sodium hydrogencarbonate was added, andthe mixture was extracted with ethyl acetate. The extract was washedwith brine, and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. The residue was purified by columnchromatography on silica gel [silica gel 100 g, chloroform/methanol(100/1→50/1)) to yield the title compound as an orange oil (5.41 g,84.9%).

¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d, J=6.6 Hz), 2.32–2.42(1H, m),2.33(3H, s), 3.98(3H, s), 4.12(2H, d, J=7.4 Hz), 7.28(1H, dd, J=7.8, 7.8Hz), 7.46(1H, dd, J=1.6, 7.8 Hz), 7.50(1H, dd, J=1.6, 10.7 Hz), 8.21(1H,s).

7) Preparation of4-carboxy-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one

To a suspension of6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one(5.27 g, 16.6 mmol) in methanol (50 mL) was added a 2 mol/L aqueoussodium hydroxide (50 mL), and the mixture was stirred at 60° C. for 15minutes. The temperature of the reaction mixture was allowed to dropback to room temperature, and then, water was added. After the systemwas acidified with concentrated hydrochloric acid, the mixture wasextracted with ethyl acetate. The extract was washed with brine, anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was recrystallized fromchloroform-hexane to yield the title compound as colorless fine-needles(4.73 g, 93.8%).

Melting point: 159.0–159.5° C. ¹H NMR(400 MHz, CDCl₃)δ: 1.02(6H, d,J=6.7 Hz), 2.33–2.42(1H, m), 2.35(3H, d, J=1.6 Hz), 4.21 (2H, d, J=7.4Hz), 7.32 (1H, dd, J=7.8, 7.8 Hz), 7.52 (1H, dd, J=1.8, 8.0 Hz),7.55(1H, dd, J=1.8, 10.6 Hz), 8.63(1H, s), 14.13(1H, s). IR(KBr) cm⁻¹:2960, 1742, 1633, 1574, 1425, 1101, 820.

8) Preparation of6-(3-fluoro-4-methylphenyl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one

To a solution of4-carboxy-6-(3-fluoro-4-methyl-phenyl)-2-isobutyl-2H-pyridazin-3-one(4.53 g, 14.9 mmol) in THF (40 mL) was added triethylamine (1.66 g, 16.4mmol). To the ice-cooled mixture was added dropwise a solution of ethylchlorocarbonate (1.78 g, 16.4 mmol) in THF (5 mL), and the mixture wasstirred for 30 minutes. Triethylamine hydrochloride was filtered off. Anice-cold solution of sodium borohydride (564 mg, 14.9 mmol) in water (1mL) was added to the filtrate, and then, the mixture was stirred at roomtemperature for 10 minutes. Thereafter, 2 mol/L hydrochloric acid wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure. The residue was purified by column chromatography on silicagel [silica gel 300 g, chloroform/methanol (100/1→50/1)) to yield thetitle compound as a colorless crystalline powder (1.08 g, 25.0%).

Melting point: 147.3–147.5° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d,J=6.6 Hz), 2.29–2.39(1H, m), 2.32(3H, d, J=1.8 Hz), 3.05(1H, t, J=6.0Hz), 4.08(2H, d, J=7.4 Hz), 4.71(2H, dd, J=1.2, 6.0 Hz), 7.26(1H, dd,J=7.8 Hz), 7.46(1H, dd, J=7.8, 7.8 Hz), 7.50(1H, dd, J=1.8, 10.8 Hz),7.65(1H, s). IR(KBr) cm⁻¹: 3330, 1644, 1596, 1514, 1226, 1087, 824.

9) Preparation of6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

To an ice-cold solution of6-(3-fluoro-4-methyl-phenyl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one(1.08 g, 3.73 mmol) in methylene chloride (20 mL) were addedtriethylamine (491 mg, 4.85 mmol) and methanesulfonyl chloride (513 mg,4.48 mmol), and the mixture was stirred for 1 hour. A saturated aqueoussolution of sodium hydrogencarbonate was added to the reaction mixture,and then, the mixture was extracted with ethyl acetate. The extract waswashed with brine and dried over anhydrous sodium sulfate. The solventwas distilled off under reduced pressure, and the residue wasrecrystallized from chloroform-hexane to yield the title compound as acolorless crystalline powder (964 mg, 70.4%).

Melting point: 142.7–143.4° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d,J=6.8 Hz), 2.30–2.34(1H, m), 2.33(3H, d, J=1.8 Hz), 3.17(3H, s),4.08(2H, d, J=7.4 Hz), 5.27(2H, d, J=1.4 Hz), 7.27(1H, dd, J=7.8, 7.8Hz), 7.45(1H, dd, J=1.8, 8.0 Hz), 7.50(1H, dd, J=1.8, 10.9 Hz), 7.76(1H,t, J=1.4 Hz). IR(KBr) cm⁻¹: 3435, 2964, 1658, 1610, 1354, 1165, 875.

10) Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)-methyl-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one

To a solution of6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one(100 mg, 0.27 mmol) in acetonitrile (1 mL) were added potassiumcarbonate (56.3 mg, 0.41 mmol) and tert-butyl 1-piperazinecarboxylate(60.7 mg, 0.33 mmol), and the mixture was stirred at 80° C. for 2 hours.The temperature of the reaction mixture was allowed to drop back to roomtemperature, and then, water was added. The mixture was extracted withchloroform. The extract was dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on silica gel [chloroform/methanol(40/1)] to yield the title compound as a yellow oil (115 mg, 92.4%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=3.4 Hz), 1.47(9H, s),2.28–2.40(1H, m), 2.33(3H, s), 2.52(4H, t, J=4.7 Hz), 3.51(4H, t, J=4.7Hz), 3.58(2H, s), 4.07 (2H, d, 4.1 Hz), 7.27 (1H, dd, J=7.6, 7.6 Hz),7.44–7.52 (2H, m), 7.77(1H, s).

Example 2 Preparation of6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-(1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

To a solution of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one(115 mg, 0.25 mmol) in ethyl acetate (2 mL) was added a 4 mol/L solution(2 mL) of hydrochloric acid in ethyl acetate, and the mixture wasstirred at 50° C. for 1 hour. The temperature of the reaction mixturewas allowed to drop back to room temperature, and then, diethyl etherwas added. The precipitate was collected to yield the title compound asa colorless crystalline powder (81.1 mg, 75.0%).

Melting point: 186.2–195.0° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:0.95(6H, d, J=6.8 Hz), 2.22–2.33(1H, m), 2.29(3H, d, J=2.0 Hz), 3.15(4H,br), 3.32(4H, t, J=5.2 Hz), 3.93(2H, s), 4.02(2H, d, J=7.1 Hz), 7.40(1H,dd, J=8.1, 8.1 Hz), 7.59–7.66(2H, m), 8.21(1H, s). IR(KBr) cm⁻¹: 1656,1610, 1425, 1306, 956. Mass m/z: 358(M⁺)

Example 3 Preparation of6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as ayellow oil (yield: 93.4%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.8 Hz), 2.28–2.40(1H, m),2.33(6H, s), 2.52(4H, br), 2.62(4H, br), 3.58(2H, s), 4.07(2H, d, J=7.4Hz), 7.27(1H, dd, J=7.9, 7.9 Hz), 7.46–7.52(2H, m), 7.75(1H, d, J=1.0Hz).

Example 4 Preparation of6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

To a solution of6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one(94.4 mg, 0.25 mmol) in methanol (1 mL) was added dropwise at roomtemperature under stirring a 4 mol/L solution (0.15 mL) of hydrochloricacid in ethyl acetate. The solvent was distilled off under reducedpressure. The residue was recrystallized from methanol-ether to yieldthe title compound as a colorless crystalline powder (71.9 mg, 63.7%).

Melting point: 248.5–252.0° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:0.94(6H, d, J=6.8 Hz), 2.29(3H, d, J=1.8 Hz), 2.22–2.33(1H, m), 2.77(3H,s), 3.18(4H, br), 3.38(4H, br), 3.91(2H, s), 4.02(2H, d, J=7.0 Hz),7.40(1H, dd, J=8.0, 8.0 Hz), 7.59–7.65(2H, m), 8.16(1H, s). IR(KBr)cm⁻¹: 1653, 1609, 1451, 1425, 951. Mass m/z: 372(M⁺)

Example 5 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as a yellowoil (yield: 84.8%).

¹H NMR(400 MHz, CDCl₃)δ: 0.96(6H, d, J=6.6 Hz), 2.27–2.38(1H, m),2.30(3H, s), 2.70(4H, t, J=5.0 Hz), 3.66(4H, t, J=5.2 Hz), 3.69(2H, s),4.06(2H, d, J=7.2 Hz), 7.23(1H, dd, J=7.9, 7.9 Hz), 7.46–7.52(2H, m),7.79(1H, s).

Example 6 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 85.9%).

Melting point: 159.7–160.7° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.96(6H, d,J=6.6 Hz), 2.20–2.34(1H, m), 2.30(3H, d, J=1.7 Hz), 3.35(4H, t, J=5.1Hz), 3.84(4H, t, J=5.1 Hz), 4.05(2H, d, J=7.0 Hz), 4.45(2H, s), 7.42(1H,dd, J=8.2, 8.2 Hz), 7.62–7.68(2H, m), 8.47(1H, s). IR(KBr) cm⁻¹: 1663,1613, 1427, 1087, 1052, 821. Mass m/z: 359(M⁺—H₂O)

Example 7 Preparation of4-dimethylaminomethyl-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one

To6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one(100 mg, 0.27 mmol) was added a 40% aqueous dimethylamine (1 mL), andthe mixture was stirred at 80° C. for 2 hours. The temperature of thereaction mixture was allowed to drop back to room temperature, and then,water was added. The mixture was extracted with chloroform. The extractwas dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure, and the residue was purified by columnchromatography on silica gel [chloroform/methanol (40/1)] to yield thetitle compound as a yellow oil (69.7 mg, 80.9%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.8 Hz), 2.23–2.41(1H, m),2.31(3H, s), 2.35(6H, s), 3.50(2H, d, J=1.2 Hz), 4.08(2H, d, J=7.4 Hz),7.26(1H, dd, J=7.9, 7.9 Hz), 7.47–7.54(2H, m), 7.76(1H, d, J=1.4 Hz).

Example 8 Preparation of4-dimethylaminomethyl-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-dimethyl-aminomethyl-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 85.4%).

Melting point: 246.5–248.5° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.96(6H, d,J=6.6 Hz), 2.23–2.34(1H, m), 2.30(3H, s), 2.81(6H, s), 4.05(2H, d, J=7.0Hz), 4.27(2H, s), 7.41(1H, dd, J=8.0, 8.0 Hz), 7.22–7.68(2H, m),8.52(1H, s). IR(KBr) cm⁻¹: 1648, 1607, 1422, 1227, 1110, 1051. Mass m/z:317(M⁺)

Example 9 Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methylaminomethyl-2H-pyridazin-3-one 1)Preparation of4-carboxy-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(7),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-onewas reacted to yield the title compound as yellow crystals (yield:98.9%).

Melting point: 169.1–170.7° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.50–0.67(4H,m), 1.40–1.50(1H, m), 3.97(3H, s), 4.23(2H, d, J=7.3 Hz), 7.07(1H, dd,J=8.5, 8.5 Hz), 7.57(1H, ddd, J=1.2, 2.2, 8.5 Hz), 7.85(1H, dd, J=2.2,12.2 Hz), 8.63(1H, s), 14.20(1H, s). IR(KBr) cm⁻¹: 1761, 1629, 1521,1476, 1461. Mass m/z: 318(M⁺)

2) Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow fine-needles(yield: 21.3%).

Melting point: 119.4–122.6° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.45–0.60(4H,m), 1.36–1.47(1H, m), 3.12(1H, t, J=6.0 Hz), 3.95(3H, s), 4.10(2H, d,J=7.3 Hz), 4.72(2H, dd, J=1.2, 5.9 Hz), 7.03(1H, dd, J=8.5, 8.5 Hz),7.51(1H, ddd, J=1.2, 2.2, 8.5 Hz), 7.62(1H, dd, J=2.2, 12.4 Hz),7.65(1H, t, J=1.2 Hz). IR(KBr) cm⁻¹: 3431, 1652, 1604, 1524. Mass m/z:304(M⁺).

3) Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow needles(yield: 80.4%).

Melting point: 156.9–158.4° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.45–0.61(4H,m), 1.36–1.46(1H, m), 3.18(3H, s), 3.95(3H, s), 4.10(2H, d, J=7.3 Hz),5.28(2H, d, J=1.2 Hz), 7.03(1H, dd, J=8.5, 8.5 Hz), 7.51(1H, ddd, J=1.2,2.2, 8.5 Hz), 7.62(1H, dd, J=2.2, 12.2 Hz), 7.76(1H, t, J=1.2 Hz).IR(KBr) cm⁻¹: 1656, 1612, 1523, 1358, 1177. Mass m/z: 382(M⁺).

4) Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methylaminomethyl-2H-pyridazin-3-one

A solution of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one(160 mg, 0.42 mmol) in 30% methylamine/ethanol (5 mL) was stirred at 80°C. for 4 hours in a sealed tube. The solvent was distilled off underreduced pressure, and the residue was purified by preparative thin-layerchromatography on silica gel [developing solvent: chloroform/methanol(10/1)] to yield title compound as a slightly yellow oil (87 mg, 65.5%).

¹H NMR(400 MHz, CDCl₃)δ: 0.45–0.59(4H, m), 1.36–1.47(1H, m), 1.85(1H,br), 2.52(3H, s), 3.80(2H, d, J=1.2 Hz), 3.95(3H, s), 4.10(2H, d, J=7.3Hz), 7.01(1H, dd, J=8.5, 8.5 Hz), 7.52(1H, ddd, J=1.2, 2.2, 8.5 Hz),7.62(1H, dd, J=2.2, 12.4 Hz), 7.66(1H, t, J=1.2 Hz). Mass m/z: 317(M⁺).

Example 10 Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methylaminomethyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methylaminomethyl-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow needles(yield: 93.8%).

Melting point: 220.8–224.3° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:0.44–0.54(4H, m), 1.29–1.40(1H, m), 2.66(3H, s), 3.91(3H, s), 4.05(2H,d, J=7.3 Hz), 4.12(2H, s), 7.33(1H, dd, J=8.5, 8.5 Hz), 7.70–7.79(2H,m), 8.39 (1H, s).

IR(KBr) cm⁻¹: 1645, 1599, 1521, 1437.

Example 11 Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand N-methylpiperazine were reacted to yield the title compound as ayellow oil (yield: 73.8%).

¹H NMR(400 MHz, CDCl₃)δ: 0.45–0.59(4H, m), 1.36–1.47(1H, m), 2.33(3H,s), 2.52(4H, br), 2.62(4H, br), 3.80(2H, d, J=1.2 Hz), 3.58(2H, d, J=1.0Hz), 3.95(3H, s), 4.09(2H, d, J=7.3 Hz), 7.04(1H, dd, J=8.5, 8.5 Hz),7.53(1H, ddd, J=1.2, 2.2, 8.5 Hz), 7.61(1H, dd, J=2.2, 12.4 Hz),7.74(1H, t, J=1.2 Hz). IR(Neat) cm⁻¹: 1652, 1608, 1520, 1456, 1440. Massm/z: 386(M⁺).

Example 12 Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow needles (yield:81.0%).

Melting point: 237.4–238.4° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:0.47–0.58(4H, m), 1.31–1.41(1H, m), 2.33(3H, s), 2.52(4H, br), 2.62(4H,br), 2.90–3.85(10H, m), 3.91(3H, s), 4.03(2H, d, J=7.3 Hz), 7.30(1H, dd,J=8.5, 8.5 Hz), 7.70–7.78(2H, m), 8.28(1H, brs). IR(KBr) cm⁻¹: 1653,1608, 1523, 1438.

Example 13 Preparation of2-cyclopropylmethyl-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 7,2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand dimethylamine were reacted to yield the title compound as a yellowoil (yield: 88.1%).

¹H NMR(400 MHz, CDCl₃)δ: 0.45–0.59(4H, m), 1.37–1.48(1H, m), 2.36(6H,s), 3.51(2H, s), 3.95(3H, s), 4.10(2H, d, J=7.3 Hz), 7.02(1H, dd, J=8.5,8.5 Hz), 7.53–7.57(1H, m), 7.64(1H, dd, J=2.2, 12.7 Hz), 7.75(1H, s).IR(Neat) cm⁻¹: 1652, 1608, 1523, 1456, 1438. Mass m/z: 331(M⁺).

Example 14 Preparation of2-cyclopropylmethyl-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,2-cyclopropylmethyl-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow needles(yield: 89.0%).

Melting point: 233.6–235.0° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:0.41–0.54(4H, m), 1.27–1.37 (1H, m), 2.83(6H, s), 3.92(3H, s), 4.06(2H,d, J=7.3 Hz), 4.30(2H, s), 7.33(1H, dd, J=8.8, 8.8 Hz), 7.69–7.77(2H,m), 8.51(1H, s). IR(KBr) cm⁻¹: 1648, 1584, 1522, 1439.

Example 15 Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(2-hydroxyethyl)aminomethyl-2H-pyridazin-3-one

Following the procedure of Example 9(4),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand 2-aminoethanol were reacted to yield the title compound as a yellowoil (yield: 72.1%).

¹H NMR(400 MHz, CDCl₃)δ: 0.44–0.59(4H, m), 1.36–1.47(1H, m), 2.86(2H, t,J=5.1 Hz), 3.73(2H, t, J=5.1 Hz), 3.84(2H, d, J=1.0 Hz), 3.94(3H, s),4.10(2H, d, J=7.3 Hz), 7.02(1H, dd, J=8.5, 8.5 Hz), 7.50–7.54(1H, m),7.62(1H, dd, J=2.2, 12.7 Hz), 7.67(1H, s). IR(Neat) cm⁻¹: 3411, 1651,1605, 1523, 1439. Mass m/z: 347(M⁺).

Example 16 Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(2-hydroxyethyl)aminomethyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(2-hydroxyethyl)aminomethyl-2H-pyridazin-3-onewas reacted to yield the title compound as pale brown needles (yield:79.2%).

Melting point: 166.8–169.3° C. (dec.) ¹H NMR(400 MHz, CDCl₃)δ:0.40–0.54(4H, m), 1.27–1.37(1H, m), 3.13(2H, br), 3.28(2H, br), 3.74(3H,s), 4.05(2H, d, J=7.1 Hz), 4.18(2H, s), 5.31(1H, br), 7.33(1H, dd,J=8.8, 8.8 Hz), 7.69–7.79(2H, m), 8.40(1H, s). IR(KBr) cm⁻¹: 3334, 1654,1616, 1604, 1523, 1441.

Example 17 Preparation of4-(4-benzyl-1-piperazinyl)methyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand 1-benzylpiperazine were reacted to yield the title compound as ayellow oil (yield: 97.7%).

¹H NMR(400 MHz, CDCl₃)δ: 0.44–0.58(4H, m), 1.36–1.46(1H, m), 2.56(4H,br), 2.62(4H, br), 3.56(2H, s), 3.58(2H, d, J=1.0 Hz), 3.95(3H, s),4.09(2H, d, J=7.1 Hz), 7.04(1H, dd, J=8.5, 8.5 Hz), 7.23–7.36(5H, m),7.50–7.55(1H, m), 7.61(1H, dd, J=2.2, 12.7 Hz), 7.75(1H, s). IR(Neat)cm⁻¹: 1652, 1608, 1522, 1438, 1289, 1237. Mass m/z: 462(M⁺).

Example 18 Preparation of4-(4-benzyl-1-piperazinyl)methyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,4-(4-benzyl-1-piperazinyl)methyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow prisms(yield: 85.7%).

Melting point: 253.0–257.9° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:0.41–0.55(4H, m), 1.27–1.38(1H, m), 3.06–3.49(10H, br), 3.56(2H, s),3.91(3H, s), 4.02(2H, d, J=7.3 Hz), 4.39(2H, brs), 7.30(1H, dd, J=8.5,8.5 Hz), 7.44–7.48(3H, m), 7.59–7.64(2H, m), 7.69–7.77(2H, m), 8.30(1H,brs). IR(KBr) cm⁻¹: 1656, 1616, 1523, 1439, 1292, 1271.

Example 19 Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand tert-butyl 1-piperazinecarboxylate were reacted to yield the titlecompound as a pale brown oil (yield: 98.9%).

¹H NMR(400 MHz, CDCl₃)δ: 0.44–0.59(4H, m), 1.47(9H, s), 1.38–1.46(1H,m), 2.53(4H, t, J=4.9 Hz), 3.51(4H, t, J=4.9 Hz), 3.58(2H, d, J=1.2 Hz),3.95(3H, s), 4.10(2H, d, J=7.3 Hz), 7.03(1H, dd, J=8.5, 8.5 Hz),7.51(1H, ddd, J=1.2, 2.2, 8.5 Hz), 7.61(1H, dd, J=2.2, 12.7 Hz),7.76(1H, s). IR(Neat) cm⁻¹: 1698, 1653, 1609, 1523, 1438, 1427. Massm/z: 472(M⁺).

Example 20 Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one

4-(4-tert-Butoxycarbonyl-1-piperazinyl)methyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazine-3-one(220 mg, 0.47 mmol) was dissolved in ice-cold trifluoroacetic acid (2mL), and at the same temperature, the mixture was stirred for 15minutes. Water (10 mL) was added to the reaction mixture. The mixturewas alkalinized with potassium carbonate and extracted twice withchloroform (20 mL). The extracts were washed with brine (20 mL) anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure. The residue was recrystallized from chloroform-hexaneto yield the title compound as pale yellow prisms (120 mg, 69.2%).

Melting point: 111.5–118.0° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.45–0.59(4H,m), 1.36–1.47(1H, m), 2.55(4H, br), 2.96(4H, t, J=4.9 Hz), 3.56(2H, d,J=1.5 Hz), 3.95(3H, s), 4.09(2H, d, J=7.3 Hz), 7.04(1H, dd, J=8.5, 8.5Hz), 7.53(1H, ddd, J=1.2, 2.2, 8.5 Hz), 7.62(1H, dd, J=2.2, 12.7 Hz),7.76(1H, t, J=1.5 Hz). IR(KBr) cm⁻¹: 3328, 1648, 1605, 1520, 1437. Massm/z: 372(M⁺).

Example 21 Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow prisms(yield: 94.5%).

Melting point: 139.1–142.4° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.42–0.56(4H,m), 1.29–1.39(1H, m), 3.40(4H, br), 3.70(4H, br), 3.91(3H, s), 4.16(2H,d, J=7.3 Hz), 4.16(2H, brs), 7.31(1H, dd, J=8.5, 8.5 Hz), 7.71–7.73(2H,m), 8.41(1H, brs). IR(KBr) cm⁻¹: 3435, 1660, 1610, 1526, 1440, 1291.

Example 22 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as a palebrown oil (yield: 83.0%).

¹H NMR(400 MHz, CDCl₃)δ: 0.43–0.58(4H, m), 1.35–1.46(1H, m), 2.71 (4H,t, J=4.9 Hz), 3.67(4H, t, J=4.9 Hz), 3.71(2H, s), 3.85(2H, br), 3.94(3H,s), 4.10(2H, d, J=7.3 Hz), 7.01(1H, dd, J=8.5, 8.5 Hz), 7.51–7.56(1H,m), 7.61(1H, dd, J=2.2, 12.4 Hz), 7.73(1H, t, J=1.5 Hz). IR(Neat) cm⁻¹:3616, 3476, 3275, 1648, 1601, 1529. Mass m/z: 391(M⁺).

Example 23 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one hydrochloride

Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow prisms (yield:75.9%).

Melting point: 175.2–176.8° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.42–0.55(4H,m), 1.28–1.39(1H, m), 3.36(4H, br), 3.82(4H, br), 3.92(3H, s), 4.06(2H,d, J=7.3 Hz), 4.49(2H, brs), 7.33(1H, dd, J=8.5, 8.5 Hz), 7.71–7.79(2H,m), 8.47(1H, brs). IR(KBr) cm⁻¹: 3162, 1652, 1604, 1531.

Example 24 Preparation of4-aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one 1)Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-phthalimidomethyl-2H-pyridazin-3-one

To a solution of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one(220 mg, 0.57 mmol) in N,N-dimethylformamide (5 mL) was added potassiumphthalimide (160 mg, 0.87 mmol), and the mixture was stirred at 80° C.for 2 hours. Water (30 mL) was added to the reaction mixture. Afterstirring under cooling over ice water, precipitated crystals werecollected by filtration, dried in air, and recrystallized fromchloroform-hexane to yield the title compound as colorless needles (202mg, 81.0%).

Melting point: 241.7–243.6° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.45–0.59(4H,m), 1.37–1.47(1H, m), 3.90(3H, s), 4.10(2H, d, J=7.1 Hz), 4.91 (2H, d,J=1.2 Hz), 6.95(1H, dd, J=8.5, 8.5 Hz), 7.29(1H, t, J=1.2 Hz), 7.38(1H,ddd, J=1.2, 2.2, 8.5 Hz), 7.48(1H, dd, J=2.2, 12.4 Hz), 7.76–7.81(2H,m), 7.90–7.95(2H, m). IR(KBr) cm⁻¹: 1712, 1653, 1614, 1524. Mass m/z:433(M⁺).

2) Preparation of4-aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

To a solution of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-phthalimidomethyl-2H-pyridazin-3-one(190 mg, 0.43 mmol) in methanol (5 mL) was added hydrazine monohydrate(110 mg, 2.20 mmol), and the mixture was heated under reflux for 2hours. Methanol was distilled off under reduced pressure, and chloroform(20 mL) was added to the residue. The mixture was successively washedwith water (10 mL) and brine (10 mL) in this order, and was then driedover anhydrous sodium sulfate. The solvent was distilled off underreduced pressure. The residue was purified by preparative thin-layerchromatography on silica gel [developing solvent: chloroform/10% w/vsolution of methanol in ammonia (20/1)] to yield the title compound aspale yellow crystals (130 mg, 97.8%).

¹H NMR(400 MHz, CDCl₃)δ: 0.45–0.59(4H, m), 1.37–1.47(1H, m), 1.51(2H,br), 3.89(2H, d, J=1.2 Hz), 3.95(3H, s), 4.11(2H, d, J=7.1 Hz), 7.02(1H,dd, J=8.5, 8.5 Hz), 7.53(1H, ddd, J=1.2, 2.4, 8.5 Hz), 7.63(1H, dd,J=2.2, 12.7 Hz), 7.68(1H, s). IR(KBr) cm⁻¹: 3393, 1651, 1606, 1523,1438, 1293. Mass m/z: 303(M⁺).

Example 25 Preparation of4-aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow needles (81.0%).

Melting point: 188.2–194.2° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:0.42–0.55(4H, m), 1.29–1.39(1H, m), 3.92(3H, s), 4.01(2H, s), 4.06(2H,d, J=7.1 Hz), 7.34(1H, dd, J=8.5, 8.5 Hz), 7.71–7.78(2H, m), 8.31(1H,s). IR(KBr) cm⁻¹: 3507, 3440, 1644, 1581, 1522, 1438.

Example 26 Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand tert-butyl 1-piperazinecarboxylate were reacted to yield the titlecompound as a yellow oil (yield: 94.3%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.6 Hz), 1.46(9H, s),2.27–2.40(1H, m), 2.52(4H, t, J=5.2 Hz), 3.50(4H, t, J=5.2 Hz), 3.57(2H,s), 3.95(3H, s), 4.06(2H, d, J=7.4 Hz), 7.03(1H, dd, J=8.6, 8.6 Hz),7.51(1H, dd, J=1.2, 8.4 Hz), 7.60(1H, dd, J=2.2, 12.5 Hz), 7.75(1H, s).

Example 27 Preparation of6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-(1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 2,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 58.5%).

Melting point: 163.0–177.0° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:0.94(6H, d, J=6.8 Hz), 2.22–2.33(1H, m), 3.17(4H, br), 3.33(4H, t, J=5.3Hz), 3.92(3H, s), 3.96(2H, s), 4.01(2H, d, J=7.1 Hz), 7.27(1H, dd,J=8.9, 8.9 Hz), 7.67–7.72(2H, m), 8.22(1H, s). IR(KBr) cm⁻¹: 1656, 1608,1522, 1440, 1291, 1113. Mass m/z: 374(M⁺).

Example 28 Preparation of6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as ayellow oil (yield: 80.9%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.8 Hz), 2.28–2.40(1H, m),2.34(3H, s), 2.55(4H, br), 2.63(4H, br), 3.58(2H, d, J=1.4 Hz), 3.95(3H,s), 4.06(2H, d, J=7.4 Hz), 7.04(1H, dd, J=8.6, 8.6 Hz), 7.53(1H, dd,J=1.2, 8.6 Hz), 7.61 (1H, dd, J=2.2, 12.5 Hz), 7.73(1H, s).

Example 29 Preparation of6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 73.3%).

Melting point: 236.9–237.0° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.94(6H, d,J=6.8 Hz), 2.21–2.32(1H, m), 2.77(3H, s), 3.14(4H, br), 3.36(4H, br),3.87(2H, s), 3.91(3H, s), 4.00(2H, d, J=7.1 Hz), 7.26(1H, dd, J=8.5, 8.5Hz), 7.66–7.71(2H, m), 8.12(1H, s). IR(KBr) cm⁻¹: 1655, 1606, 1524,1440, 1291, 1113, 1022. Mass m/z: 388(M⁺)

Example 30 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as a yellowoil (yield: 87.2%).

¹H NMR(400 MHz, CDCl₃)δ: 0.96(6H, d, J=6.8 Hz), 2.27–2.39(1H, m),2.71(4H, t, J=5.0 Hz), 3.67(4H, t, J=5.0 Hz), 3.70(2H, s), 3.93(3H, s),4.07(2H, d, J=7.4 Hz), 7.01(1H, dd, J=8.6, 8.6 Hz), 7.53(1H, dd, J=1.4,8.4 Hz), 7.61(1H, dd, J=2.2, 12.5 Hz), 7.72(1H, s).

Example 31 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless flakes (yield:89.0%).

Melting point: 129.8–133.1° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.95(6H, d,J=6.8 Hz), 2.23–2.34(1H, m), 3.34(4H, t, J=5.1 Hz), 3.83(4H, t, J=5.2Hz), 3.92(3H, s), 4.03(2H, d, J=7.0 Hz), 4.44(2H, s), 7.29(1H, dd,J=8.7, 8.7 Hz), 7.69–7.75(2H, m), 8.46(1H, s). IR(KBr) cm⁻¹: 1652, 1601,1525, 1440, 1277. Mass m/z: 362(M⁺—CH₂OH)

Example 32 Preparation of4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 7,6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand dimethylamine were reacted to yield the title compound as a yellowoil (yield: 88.6%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.8 Hz), 2.30–2.40(1H, m),2.36(6H, s), 3.50(2H, s), 3.93(3H, s), 4.07(2H, d, J=7.2 Hz), 7.02(1H,dd, J=8.6, 8.6 Hz), 7.55(1H, d, J=8.6 Hz), 7.63(1H, dd, J=2.1, 12.5 Hz),7.75(1H, s).

Example 33 Preparation of4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless needles (yield:81.0%).

Melting point: 212.4–212.8° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.95(6H, d,J=6.8 Hz), 2.23–2.33(1H, m), 2.81(6H, s), 3.92(3H, s), 4.04(2H, s, J=7.1Hz), 4.27(2H, s), 7.29(1H, dd, J=8.1, 8.1 Hz), 7.70–7.75(2H, m),8.51(1H, s). IR(KBr) cm⁻¹: 1652, 1607, 1522, 1439, 1292, 1112. Mass m/z:333(M⁺)

Example 34 Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one 1)Preparation of 4-methoxycarbonyl-6-phenyl-2H-pyridazin-3-one

Following the procedure of Example 1(5),4-carboxy-6-phenyl-2H-pyridazin-3-one was reacted to yield the titlecompound as pale yellow crystals (yield: 98.9%).

Melting point: 202.5–206.2° C. (dec.) ¹H NMR(400 MHz, CDCl₃)δ: 4.01(3H,s), 7.45–7.54(3H, m), 7.78–7.85(2H, m), 8.38(1H, s), 11.86(1H, br)IR(KBr) cm⁻¹: 1717, 1670, 1443, 1259. Mass m/z: 230(M⁺).

2) Preparation of2-isobutyl-4-methoxycarbonyl-6-phenyl-2H-pyridazin-3-one

Following the procedure of Example 1(6),4-methoxycarbonyl-6-phenyl-2H-pyridazin-3-one was reacted to yield thetitle compound as a yellow oil (yield: 94.1%).

¹H NMR(400 MHz, CDCl₃)δ: 1.00(6H, d, J=6.6 Hz), 2.33–2.44(1H, m),3.98(3H, s), 4.14(2H, d, J=7.4 Hz), 7.42–7.51(3H, m), 7.79–7.83(2H, m),8.27(1H, s).

3) Preparation of 4-carboxy-2-isobutyl-6-phenyl-2H-pyridazin-3-one

Following the procedure of Example 1(7),2-isobutyl-4-methoxycarbonyl-6-phenyl-2H-pyridazin-3-one was reacted toyield the title compound as colorless fine-needles (yield: 82.5%).

Melting point: 120.5–121.0° C. ¹H NMR(400 MHz, CDCl₃)δ: 1.03(6H, d,J=6.6 Hz), 2.34–2.45(1H, m), 4.23(2H, d, J=7.4 Hz) 7.49–7.54 (3H,m),7.84–7.89 (2H,m), 8.69 (1H,s), 14.20 (1H, s). IR(KBr) cm⁻¹: 3448, 2956,1741, 1636, 1418, 1116. Mass m/z: 272(M⁺)

4) Preparation of 4-hydroxymethyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-isobutyl-6-phenyl-2H-pyridazin-3-one was reacted to yieldthe title compound as colorless fine-needles (yield: 22.3%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.6 Hz), 2.29–2.40(1H, m),3.67(1H, br), 4.08(2H, d, J=7.4 Hz), 4.72(2H, d, J=3.9 Hz),7.39–7.49(3H, m), 7.76(1H, t, J=1.4 Hz), 7.79–7.84(2H, m).

5) Preparation of2-isobutyl-4-methanesulfonyloxymethyl-6-phenyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),4-hydroxymethyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one was reacted toyield the title compound as colorless fine-needles (yield: 68.4%).

Melting point: 129.7° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d, J=6.6 Hz),2.30–2.41(1H, m), 3.17(3H, s), 4.10(2H, d, J=7.2 Hz), 5.28(2H, d, J=1.2Hz), 7.43–7.52(3H, m), 7.79–7.82(3H, m). IR(KBr) cm⁻¹: 3442, 2963, 1658,1611, 1355, 1165, 872. Mass m/z: 336(M⁺)

6) Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)-methyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-isobutyl-4-methanesulfonyloxymethyl-6-phenyl-2H-pyridazin-3-one andtert-butyl 1-piperazinecarboxylate were reacted in N,N-dimethylformamideas a solvent to yield the title compound as a yellow oil (yield: 83.5%).

¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d, J=6.8 Hz), 1.47(9H, s), 2.53(4H, t,J=4.9 Hz), 3.50(4H, t, J=4.9 Hz), 3.59(2H, d, J=1.0 Hz), 4.09(2H, d,J=7.2 Hz), 7.40–7.50(3H, m), 7.80–7.84(3H, m).

Example 35 Preparation of2-isobutyl-6-phenyl-4-(1-piperazinyl)-methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 2,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-isobutyl-6-phenyl-2H-pyridazin-3-onewas reacted to yield the title compound as a white solid (yield: 67.9%).

Melting point: 154.3–159.5° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.94(6H, d,J=6.8 Hz), 2.20–2.32(1H,m), 2.86(4H,br), 3.21(4H, br), 3.71(2H, s),4.01(2H, d, J=7.2 Hz), 7.42–7.53(3H, m), 7.84–7.89(2H, m), 7.96(1H, s).IR(KBr) cm⁻¹: 1656, 1610, 1445, 694. Mass m/z: 326(M⁺)

Example 36 Preparation of2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-6-phenyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-isobutyl-4-methanesulfonyloxymethyl-6-phenyl-2H-pyridazin-3-one andN-methylpiperazine were reacted to yield the title compound as a yellowoil (yield: 77.1%).

¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d, J=6.8 Hz), 2.30–2.40(1H, m),2.34(3H, s), 2.55(4H, br), 2.64(4H, br), 3.59(2H, d, J=1.4 Hz), 4.08(2H,d, J=7.2 Hz), 7.40–7.50(3H, m), 7.78–7.84(3H, m).

Example 37 Preparation of2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-6-phenyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-6-phenyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 66.3%).

Melting point: 243.8–244.3° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.95(6H, d,J=6.8 Hz), 2.22–2.34(1H, m), 2.76(3H, s), 3.01(4H, br), 3.30(4H, br),3.77(2H, s), 4.02(2H, d, J=7.2 Hz), 7.43–7.53(3H, m), 7.85–7.89(2H, m),8.02(1H, s). IR(KBr) cm⁻¹: 2960, 1653, 1610, 1446. Mass m/z: 340(M⁺)

Example 38 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-isobutyl-4-methanesulfonyloxymethyl-6-phenyl-2H-pyridazin-3-one anddiethanolamine were reacted to yield the title compound as a yellow oil(yield: 38.7%).

¹H NMR(400 MHz, CDCl₃)δ: 0.97(6H, d, J=6.6 Hz), 2.29–2.40(1H, m),2.79(4H, br), 3.70(4H, br), 3.80(2H, s), 4.09(2H, d, J=7.4 Hz),7.39–7.48(3H, m), 7.81–7.87(3H, m)

Example 39 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-phenyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-phenyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless flakes (yield:68.4%).

Melting point: 131.6–132.0° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.96(6H, d,J=6.6 Hz), 2.25–2.35(1H, m), 3.35(4H, t, J=5.1 Hz), 3.84(4H, t, J=5.4Hz), 4.06(2H, d, J=7.1 Hz), 4.47(2H, s), 7.45–7.54(3H, m), 7.90–7.94(2H,m), 8.48(1H, s). IR(KBr) cm⁻¹: 1655, 1610, 1421, 1053. Mass m/z:314(M⁺—CH₂OH)

Example 40 Preparation of4-dimethylaminomethyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one

Following the procedure of Example 7,2-isobutyl-4-methanesulfonyloxymethyl-6-phenyl-2H-pyridazin-3-one anddimethylamine were reacted to yield the title compound as a yellow oil(yield: 81.1%).

¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d, J=6.8 Hz), 2.32–2.41(1H, m),2.35(6H, s), 3.51(2H, d, J=1.2 Hz), 4.09(2H, d, J=7.2 Hz), 7.38–7.48(3H,m), 7.80–7.87(3H, m).

Example 41 Preparation of4-dimethylaminomethyl-2-isobutyl-6-phenyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-dimethylaminomethyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one was reactedto yield the title compound as pale yellow flakes (yield: 71.5%).

Melting point: 221.7–222.3° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.96(6H, d,J=6.8 Hz), 2.24–2.35(1H, m), 2.82(6H, s), 4.06(2H, d, J=7.1 Hz),4.29(2H, s), 7.44–7.54(3H, m), 7.90–7.94(2H, m), 8.54(1H, s). IR(KBr)cm⁻¹: 1648, 1610, 1460, 1052. Mass m/z: 285(M⁺)

Example 42 Preparation of4-(4-benzyl-1-piperazinyl)methyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one 1)Preparation of2-isobutyl-4-methoxycarbonyl-6-(4-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(6),4-methoxycarbonyl-6-(4-methylphenyl)-2H-pyridazin-3-one was reacted toyield the title compound as slightly yellow needles (yield: 91.6%).

Melting point: 67.0–70.1° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d, J=6.6Hz), 2.32–2.43(1H, m), 2.41(3H, s), 3.98(3H, s), 4.13(2H, d, J=7.3 Hz),7.28(2H, d, J=8.3 Hz), 7.70(2H, d, J=8.3 Hz), 8.24(1H, s). IR(KBr) cm⁻¹:1718, 1663, 1605. Mass m/z: 300(M⁺)

2) Preparation of4-carboxy-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(7),2-isobutyl-4-methoxycarbonyl-6-(4-methylphenyl)-2H-pyridazin-3-one wasreacted to yield the title compound as slightly yellow needles (yield:86.7%).

Melting point: 162.1–165.4° C. ¹H NMR(400 MHz, CDCl₃)δ: 1.02(6H, d,J=6.8 Hz), 2.34–2.44(1H, m), 2.47(3H, s), 4.21(2H, d, J=7.3 Hz), 7.31(2H, d, J=8.3 Hz), 7.75 (2H, d, J=8.3 Hz), 8.66(1H, s), 14.26(1H, s).IR(KBr) cm⁻¹: 1740, 1633, 1571, 1425. Mass m/z: 286(M⁺).

3) Preparation of4-hydroxymethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one was reactedto yield the title compound as slightly yellow needles (yield: 46.0%).

Melting point: 121.9–123.5° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d,J=6.8 Hz), 2.30–2.40(1H, m), 2.40(3H, s), 3.22(1H, br), 4.08(2H, d,J=7.3 Hz), 4.71(2H, s), 7.27(2H, d, J=8.3 Hz), 7.77(1H, s), 7.70(2H, d,J=8.3 Hz). IR(KBr) cm⁻¹: 3334, 1645, 1596, 1522. Mass m/z: 272(M⁺).

4) Preparation of2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(9),4-hydroxymethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one wasreacted to yield the title compound as slightly yellow needles (yield:87.4%).

Melting point: 132.0–135.5° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d,J=6.6 Hz), 2.29–2.39(1H, m), 2.41(3H, s), 3.17 (3H, s), 4.08(2H, d,J=7.6 Hz), 5.27(2H, t, J=1.5 Hz), 7.27(2H, d, J=8.3 Hz), 7.72(2H, d,J=8.3 Hz), 7.79(1H, t, J=11.5 Hz). IR(KBr) cm⁻¹: 1656, 1609, 1355, 1166.Mass m/z: 350(M⁺).

5) Preparation of4-(4-benzyl-1-piperazinyl)methyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-oneand 1-benzylpiperazine were reacted to yield the title compound as apale yellow oil (yield: 97.7%).

¹H NMR(400 MHz, CDCl₃)δ: 0.97(6H, d, J=6.8 Hz), 2.29–2.39(1H, m),2.41(3H, s), 2.55(4H, br), 2.61 (4H, br), 3.54 (2H, s), 3.57 (2H, d,J=1.5 Hz), 4.07 (2H, d, J=7.3 Hz), 7.22–7.36(7H, m), 7.70(2H, d, J=8.3Hz), 7.77(1H, t, J=1.5 Hz). IR(Neat) cm⁻¹: 1657, 1652, 1518, 1455. Massm/z: 430(M⁺).

Example 43 Preparation of4-(4-benzyl-1-piperazinyl)methyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,4-(4-benzyl-1-piperazinyl)methyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as colorless needles (yield:91.8%).

Melting point: 253.5–260.1° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:0.92(6H, d, J=6.6 Hz), 2.18–2.28 (1H, m), 2.34(3H, s), 3.43(10H, br),3.99(2H, d, J=7.3 Hz), 4.36(2H, brs), 7.22(2H, d, J=8.1 Hz),7.43–7.49(3H, m), 7.58–7.65(2H, m), 7.78(2H, d, J=8.1 Hz), 8.30(1H,brs). IR(KBr) cm⁻¹: 1660, 1617, 1452.

Example 44 Preparation of4-dimethylaminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 7,2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-oneand dimethylamine were reacted to yield the title compound as a slightlyyellow oil (yield: 96.6%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.8 Hz), 2.38–2.41(1H, m),2.35(6H, s), 2.40(3H, s), 3.50(2H, d, J=1.5 Hz), 4.08(2H, d, J=7.3 Hz),7.26(2H, d, J=8.1 Hz), 7.73(2H, d, J=8.1 Hz), 7.78(1H, t, J=1.5 Hz).IR(Neat) cm⁻¹: 1652, 1609, 1518, 1455. Mass m/z: 299(M⁺).

Example 45 Preparation of4-dimethylaminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-dimethylaminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as colorless needles (yield:91.8%).

Melting point: 237.6–239.6° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.94(6H, d,J=6.8 Hz), 2.19–2.30(1H, m), 2.37(3H, s), 2.81(6H, s), 4.02(2H, d, J=7.0Hz), 4.30(2H, s), 7.34(2H, d, J=8.1 Hz), 7.81(2H, d, J=8.1 Hz), 8.46(1H,s). IR(KBr) cm⁻¹: 1648, 1605, 1460, 1421.

Example 46 Preparation of4-diethylaminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 9(4),2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-oneand diethylamine were reacted to yield the title compound as a paleyellow oil (yield: 95.0%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98 (6H, d, J=6.8 Hz), 1.07 (6H, t, J=7.1 Hz),2.30–2.42 (1H, m), 2.40(3H, s), 2.60(4H, q, J=7.1 Hz), 3.60(2H, d, J=1.5Hz), 4.08(2H, d, J=7.3 Hz), 7.26(2H, d, J=8.1 Hz), 7.73(2H, d, J=8.1Hz), 7.89(1H, t, J=1.5 Hz). IR(Neat) cm⁻¹: 1652, 1609, 1518, 1465, 1455.Mass m/z: 327(M⁺).

Example 47 Preparation of4-diethylaminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-diethylaminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow needles(yield: 93.8%).

Melting point: 203.9–207.0° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.94(6H, d,J=6.6 Hz), 1.27(6H, t, J=7.2 Hz), 2.20–2.30(1H, m), 2.37(3H, s),3.09–3.24(4H, m), 4.03(2H, d, J=7.1 Hz), 4.28(2H, d, J=5.4 Hz), 7.34(2H,d, J=8.1 Hz), 7.82(2H, d, J=8.1 Hz), 8.55(1H, s). IR(KBr) cm⁻¹: 1652,1610, 1523, 1481, 1468.

Example 48 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as a paleyellow oil (yield: 95.0%).

¹H NMR(400 MHz, CDCl₃)δ: 0.97(6H, d, J=6.6 Hz), 2.28–2.41(1H, m),2.40(3H, s), 2.71(4H, t, J=5.0 Hz), 3.66(4H, t, J=5.0 Hz), 3.70(2H, s),3.78(2H, br), 4.09(2H, d, J=7.6 Hz), 7.26(2H, d, J=8.1 Hz), 7.68(1H, s),7.70(2H, d, J=8.1 Hz). IR(Neat) cm⁻¹: 3392, 1645, 1600, 1520. Mass m/z:341 (M⁺—H₂O)

Example 49 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-methylphenyl)-2-isobutyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-methylphenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow needles(yield: 86.4%).

Melting point: 158.9–161.5° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:0.94(6H, d, J=6.6 Hz), 2.19–2.30(1H, m), 2.37(3H, s), 3.27–3.46(4H, m),3.77–3.85(4H, m), 4.02(2H, d, J=7.3 Hz), 4.50(2H, brs), 5.35(2H, br),7.34(2H, d, J=8.1 Hz), 7.81(2H, d, J=8.1 Hz), 8.46(1H, s). IR(KBr) cm⁻¹:3292, 1664, 1615, 1423.

Example 50 Preparation of4-aminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one 1)Preparation of2-isobutyl-6-(4-methylphenyl)-4-phthalimidomethyl-2H-pyridazin-3-one

Following the procedure of Example 24(1),2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as colorless needles (yield:98.2%).

Melting point: 221.6–223.8° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d,J=6.6 Hz), 2.27–2.41(1H, m), 2.36(3H, s), 4.08(2H, d, J=7.3 Hz), 4.91(2H, d, J=1.5 Hz), 7.20(2H, d, J=8.1 Hz), 7.32(1H, t, J=1.5 Hz),7.56(2H, d, J=8.1 Hz), 7.75–7.80(2H, m), 7.89–7.94(2H, m). IR(KBr) cm⁻¹:1767, 1721, 1655, 1616. Mass m/z: 401(M⁺).

2) Preparation of4-aminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 24(2),2-isobutyl-6-(4-methylphenyl)-4-phthalimidomethyl-2H-pyridazin-3-one wasreacted to yield the title compound as colorless prisms (yield: 98.1%).

Melting point: 74.9–77.9° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.9Hz), 1.68(2H, br), 2.28–2.42(1H, m), 2.40(3H, s), 3.87(2H, d, J=1.2 Hz),4.07 (2H, d, J=7.3 Hz), 7.26(2H, d, J=8.0 Hz), 7.69(1H, t, J=1.5 Hz),7.71(2H, d, J=8.0 Hz). IR(KBr) cm⁻¹: 3363, 3289, 1648, 1604, 1519. Massm/z: 271(M⁺).

Example 51 Preparation of4-aminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-aminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one wasreacted to yield the title compound as pale yellow prisms (yield:93.1%).

Melting point: 207.4–209.4° C. (dec.) ¹H NMR(400 MHz, DMSO-d₅)δ:0.93(6H, d, J=6.6 Hz), 2.19–2.30(1H, m), 2.37(3H, s), 4.01(2H, d, J=7.1Hz), 4.02 (2H, s), 7.34(2H, d, J=8.1 Hz), 7.80(2H, d, J=8.1 Hz),8.26(1H, s). IR(KBr) cm⁻¹: 1655, 1616, 1520, 1467.

Example 52 Preparation of4-(1,3-dihydroxypropan-2-yl)aminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-oneand 2-amino-1,3-propanediol were reacted to yield the title compound ascolorless needles (yield: 83.7%).

Melting point: 134.1–135.2° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.97(6H, d,J=6.6 Hz), 2.29–2.39(1H, m), 2.40(3H, s), 2.60(3H, br), 2.82–2.87(1H,m), 3.64(2H, dd, J=5.6, 11.2 Hz), 3.80 (2H, dd, J=4.5, 11.2 Hz),3.86(2H, d, J=1.0 Hz), 4.07(2H, d, J=7.3 Hz), 7.26(2H, d, J=8.1 Hz),7.71(2H, d, J=8.1 Hz), 7.74(1H, s). IR(KBr) cm⁻¹: 3408, 3293, 1641,1592, 1520. Mass m/z: 345(M⁺).

Example 53 Preparation of4-(1,3-dihydroxypropan-2-yl)aminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-(1,3-dihydroxypropan-2-yl)aminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as colorless needles (yield:95.7%).

Melting point: 191.2–193.0° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.93(6H, d,J=6.6 Hz), 2.19–2.30(1H, m), 2.37(3H, s), 3.29(1H, br), 3.60–3.78(4H,m), 4.02(2H, d, J=7.1 Hz), 4.29(2H, s), 5.40(2H, brs), 7.34(2H, d, J=8.1Hz), 7.81(2H, d, J=8.1 Hz), 8.38(1H, s). IR(KBr) cm⁻¹: 3392, 1652, 1610.

Example 54 Preparation of2-isobutyl-4-methylaminomethyl-6-(4-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 9(4),2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-oneand methylamine were reacted to yield the title compound as a slightlyyellow oil (yield: 94.5%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.6 Hz), 1.87(1H, br),2.29–2.42(1H, m), 2.40(3H, s), 2.50(3H, s), 3.76(2H, d, J=1.2 Hz),4.07(2H, d, J=7.3 Hz), 7.26(2H, d, J=8.1 Hz), 7.67(1H, t, J=1.2 Hz),7.71(2H, d, J=8.1 Hz). IR(Neat) cm⁻¹: 3317, 1652, 1607. Mass m/z:285(M⁺).

Example 55 Preparation of2-isobutyl-4-methylaminomethyl-6-(4-methylphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,2-isobutyl-4-methylaminomethyl-6-(4-methylphenyl)-2H-pyridazin-3-one wasreacted to yield the title compound as colorless needles (yield: 97.5%).

Melting point: 198.3–201.0° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.94(6H, d,J=6.8 Hz), 2.20–2.31(1H, m), 2.37(3H, s), 2.65(3H, s), 4.02(2H, d, J=7.3Hz), 4.12(2H, s), 7.34(2H, d, J=8.1 Hz), 7.80(2H, d, J=8.1 Hz), 8.35(1H,s). IR(KBr) cm⁻¹: 3085, 1652, 1612.

Example 56 Preparation of4-(2-hydroxyethyl)aminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 9(4),2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-oneand 2-aminoethanol were reacted to yield the title compound as aslightly yellow oil (yield: 80.3%). ¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d,J=6.8 Hz), 2.20–2.38(3H, m), 2.39(3H, s), 2.84(2H, t, J=5.1 Hz),3.72(2H, t, J=5.1 Hz), 3.82(2H, d, J=1.2 Hz), 4.07(2H, d, J=7.3 Hz),7.26(2H, d, J=8.1 Hz), 7.68(1H, s), 7.70(2H, d, J=8.1 Hz). IR(Neat)cm⁻¹: 3429, 1652, 1601, 1519. Mass m/z: 315(M⁺).

Example 57 Preparation of4-(2-hydroxyethyl)aminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-(2-hydroxyethyl)aminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as colorless needles (yield:93.4%).

Melting point: 190.8–191.9° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.94(6H, d,J=6.6 Hz), 2.20–2.31(1H, m), 2.37(3H, s), 3.12(2H, t, J=5.4 Hz),3.70–3.76(2H, m), 4.02(2H, d, J=7.3 Hz), 4.18(2H, s), 5.30(1H, br),7.34(2H, d, J=8.3 Hz), 7.81(2H, d, J=8.3 Hz), 8.36(1H, s). IR(KBr) cm⁻¹:3491, 1652, 1611.

Example 58 Preparation of 4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one 1)Preparation of ethyl2-ethoxycarbonyl-2-hydroxy-4-(4-trifluoromethylphenyl)-4-oxobutanoate

Following the procedure of Example 1(3),4′-(trifluoromethyl)acetophenone was reacted to yield the title compoundas pale yellow crystals (yield: 80.8%).

¹H NMR(400 MHz, CDCl₃)δ: 1.30(6H, t, J=7.1 Hz), 3.85(2H, s), 4.22(1H,s), 4.31(4H, q, J=7.1 Hz), 7.76 (2H, d, J=8.6 Hz), 8.07 (2H, d, J=8.6Hz). IR(KBr) cm⁻¹: 3446, 1750, 1727, 1691. Mass m/z: 343(M⁺—H₂O).

2) Preparation of4-carboxy-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(4), ethyl2-ethoxycarbonyl-2-hydroxy-4-(4-trifluoromethylphenyl)-4-oxobutanoatewas reacted to yield the title compound as a pale brown crystallinepowder (yield: 91.4%).

3) Preparation of4-methoxycarbonyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(5),4-carboxy-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one was reacted toyield the title compound as a slightly yellow crystalline powder (yield:88.5%).

¹H NMR(400 MHz, CDCl₃)δ: 4.02(3H, s), 7.75(2H, d, J=8.2 Hz), 7.95(2H, d,J=8.2 Hz), 8.39(1H, s), 11.69(1H, br). IR(KBr) cm⁻¹: 3218, 3140, 3097,1720, 1678, 1326. Mass m/z: 298(M⁺).

4) Preparation of2-isobutyl-4-methoxycarbonyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(6),4-methoxycarbonyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one wasreacted to yield the title compound as yellow crystals (yield: 82.2%).

¹H NMR(400 MHz, CDCl₃)δ: 1.00(6H, d, J=6.6 Hz), 2.32–2.43(1H, m),3.99(3H, s), 4.15(2H, d, J=7.2 Hz), 7.74(2H, d, J=8.4 Hz), 7.93(2H, d,J=8.4 Hz), 8.12(1H, s). IR(Neat) cm⁻¹: 2961, 1746, 1670, 1327, 1115,1068. Mass m/z: 354(M⁺).

5) Preparation of4-carboxy-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(7),2-isobutyl-4-methoxycarbonyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as colorless fine-needles(yield: 91.6%).

Melting point: 184.4–185.0° C. ¹H NMR(400 MHz, CDCl₃)δ: 1.03(6H, d,J=6.6 Hz), 2.34–2.45(1H, m), 4.25(2H, d, J=7.2 Hz), 7.78(2H, d, J=8.2Hz), 7.99(2H, d, J=8.2 Hz), 8.70(1H, s), 14.02(1H, s). IR(KBr) cm⁻¹:3447, 1739, 1631, 1570, 1330, 1174, 1114, 1070, 847. Mass m/z: 340(M⁺)

6) Preparation of4-hydroxymethyl-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one wasreacted to yield the title compound as colorless fine-needles (yield:28.1%).

Melting point: 145.8–146.5° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d,J=6.8 Hz), 2.30–2.41(1H, m), 2.96(1H, t, J=5.9 Hz), 4.11(2H, d, J=7.4Hz), 4.74(2H, dd, J=1.4, 5.8 Hz), 7.70–7.74(3H, m), 7.94(2H, d, J=8.2Hz). IR(KBr) cm⁻¹: 3339, 1646, 1596, 1328, 1131, 1070, 848.

7) Preparation of2-isobutyl-4-methanesulfonyloxymethyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(9),4-hydroxymethyl-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as colorless fine-needles(yield: 89.9%).

Melting Point: 122.9–123.8° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d,J=6.6 Hz), 2.29–2.40(1H, m), 3.18(3H, s), 4.11(2H, d, J=7.2 Hz),5.29(2H, d, J=1.4 Hz), 7.73(2H, d, J=8.2 Hz), 7.83(1H, t, J=1.4 Hz),7.93(2H, d, J=8.2 Hz). IR(KBr) cm⁻¹: 3447, 1659, 1613, 1359, 1329, 1169,1123, 1071, 846. Mass m/z: 404(M⁺)

8) Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-isobutyl-4-methanesulfonyloxymethyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate werereacted to yield the title compound as a yellow oil (yield: 83.5%).

¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d, J=6.6 Hz), 1.47(9H, s),2.29–2.41(1H, m), 2.53(4H, t, J=4.9 Hz), 3.51(4H, t, J=4.8 Hz), 3.60(2H,s), 4.10(2H, d, J=7.4 Hz), 7.72(2H, d, J=8.2 Hz), 7.84(1H, s), 7.94(2H,d, J=8.2 Hz).

Example 59 Preparation of2-isobutyl-4-(1-piperazinyl)methyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 2,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 95.0%).

Melting point: 210.8–212.5° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.96(6H, d,J=6.6 Hz), 2.22–2.35(1H,m), 3.12(4H,br), 3.30(4H, t, J=5.2 Hz), 3.92(2H,s), 4.05(2H, d, J=7.1 Hz), 7.84(2H, d, J=8.3 Hz), 8.11(2H, d, J=8.1 Hz),8.25(1H, s). IR(KBr) cm⁻¹: 1656, 1608, 1328, 1125, 1069. Mass m/z:394(M⁺)

Example 60 Preparation of2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-isobutyl-4-methanesulfonyloxymethyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as ayellow oil (yield: 81.1%).

¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d, J=6.6 Hz), 2.30–2.41(1H, m),2.33(3H, s), 2.53(4H, br), 2.63(4H, br), 3.60(2H, s), 4.10(2H, d, J=7.2Hz), 7.72(2H, d, J=8.2 Hz), 7.83(1H, s), 7.94(2H, d, J=8.2 Hz).

Example 61 Preparation of2-isobutyl-4-(4-methyl-1-piperazinyl)-methyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as colorless flakes (yield:88.6%).

Melting point: 249.9–252.8° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.95(6H, d,J=6.8 Hz), 2.22–2.35(1H, m), 2.77(3H, s), 3.14(4H, br), 3.35(4H, br),3.88(2H, s), 4.05(2H, d, J=7.2 Hz), 7.84(2H, d, J=8.2 Hz), 8.10(2H, d,J=8.0 Hz), 8.19(1H, s). IR(KBr) cm⁻¹: 2966, 1653, 1610, 1328, 1125,1069. Mass m/z: 408(M⁺)

Example 62 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-isobutyl-4-methanesulfonyloxymethyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as a yellowoil (yield: 79.5%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.6 Hz), 2.29–2.40(1H, m),2.72(4H, br), 3.67(4H, t, J=4.2 Hz), 3.72(2H, s), 4.10(2H, d, J=7.4 Hz),7.70(2H, d, J=7.6 Hz), 7.82(1H, s), 7.94(2H, d, J=8.2 Hz).

Example 63 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 58.2%).

Melting point: 134.9–135.4° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.97(6H, d,J=6.6 Hz), 2.25–2.36(1H, m), 3.34(4H, br), 3.83(4H, t, J=5.1 Hz),4.07(2H, d, J=7.0 Hz), 4.46(2H, s), 7.86(2H, d, J=8.2 Hz), 8.13(2H, d,J=8.2 Hz), 8.55(1H, s). IR(KBr) cm⁻¹: 1653, 1605, 1319, 1125, 1069. Massm/z: 395(M⁺—H₂O)

Example 64 Preparation of4-dimethylaminomethyl-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 7,2-isobutyl-4-methanesulfonyloxymethyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 80.7%).

¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d, J=6.6 Hz), 2.31–2.40(1H, m),2.36(6H, s), 3.51(2H, d, J=1.2 Hz), 4.10(2H, d, J=7.4 Hz), 7.71(2H, d,J=8.4 Hz), 7.83(1H, t, J=1.4 Hz), 7.97(2H, d, J=8.2 Hz).

Example 65 Preparation of4-dimethylaminomethyl-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-dimethylaminomethyl-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow flakes (yield:93.0%).

Melting point: 242.2–242.3° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.97(6H, d,J=6.6 Hz), 2.25–2.36(1H, m), 2.83(6H, s), 4.07(2H, d, J=7.3 Hz),4.30(2H, s), 7.86(2H, d, J=8.3 Hz), 8.14(2H, d, J=8.0 Hz), 8.61(1H, s).IR(KBr) cm⁻¹: 2963, 1646, 1606, 1321, 1115, 1069. Mass m/z: 353(M⁺)

Example 66 Preparation of6-(4-biphenylyl)-4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-isobutyl-2H-pyridazin-3-one 1)Preparation of ethyl4-(4-biphenylyl)-2-ethoxycarbonyl-2-hydroxy-4-oxobutanoate

Following the procedure of Example 1(3), 4-acetylbiphenyl was reacted toyield the title compound as colorless flakes (yield: 83.3%).

Melting point: 88.0–88.3° C. ¹H NMR(400 MHz, CDCl₃)δ: 1.31(6H, t, J=7.1Hz), 3.87(2H, s), 4.32(4H, q, 7.1 Hz), 7.41(1H, tt, J=1.4, 7.2 Hz),7.48(2H, dd, J=7.2, 7.2 Hz), 7.63(2H, d, J=7.0 Hz), 7.70(2H, d, J=8.6Hz), 8.04(2H, d, J=8.6 Hz). IR(KBr) cm⁻¹: 3449, 1736, 1680, 1604, 1301,1244, 1204, 763.

2) Preparation of 6-(4-biphenylyl)-4-carboxy-2H-pyridazin-3-one

Following the procedure of Example 1(4), ethyl4-(4-biphenylyl)-2-ethoxycarbonyl-2-hydroxy-4-oxobutanoate was reactedto yield the title compound as a yellow crystalline powder (yield:90.2%).

Melting point: 299.7–300.8° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:7.40(1H, t, J=7.4 Hz), 7.49(2H, dd, J=7.4, 7.4 Hz), 7.74(2H, d, J=7.2Hz), 7.82(2H, d, J=8.4 Hz), 8.03(2H, d, J=8.4 Hz), 8.54(1H, s). IR(KBr)cm⁻¹: 1753, 1652, 1590, 1446, 1201, 768.

3) Preparation of 6-(4-biphenylyl)-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of Example 1(5),6-(4-biphenylyl)-4-carboxy-2H-pyridazin-3-one was reacted to yield thetitle compound as a pale yellow crystalline powder (yield: 90.4%).

Melting point: 277.0–277.9° C. (dec.) ¹H NMR(400 MHz, CDCl₃)δ: 4.01(3H,s), 7.39–7.45(3H, m), 7.64(2H, d, J=7.2 Hz), 7.72(2H, d, J=8.2 Hz),7.89(2H, d, J=8.0 Hz), 8.42(1H, s), 10.7(1H, s). IR(KBr) cm⁻¹: 2954,1727, 1671, 1594, 1265, 1098, 768.

4) Preparation of6-(4-biphenylyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(4-biphenylyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reacted toyield the title compound as yellow crystals (yield: 62.7%).

Melting point: 186.2–195.0° C. ¹H NMR(400 MHz, CDCl₃)δ: 1.01(6H, d,J=6.8 Hz), 2.34–2.45(1H, m), 3.99(3H, s), 4.16(2H, d, J=7.4 Hz),7.39(1H, tt, J=1.4, 7.4 Hz), 7.48(2H, dd, J=7.2, 7.2 Hz), 7.64(2H, d,J=7.0 Hz), 7.71(2H, d, J=8.6 Hz), 7.89(2H, d, J=8.6 Hz), 8.31(1H, s).

5) Preparation of6-(4-biphenylyl)-4-carboxy-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 1(7),6-(4-biphenylyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one wasreacted to yield the title compound as a colorless crystalline powder(yield: 79.2%).

Melting point: 156.9–157.6° C. ¹H NMR(400 MHz, CDCl₃)δ: 1.04(6H, d,J-6.6 Hz), 2.36–2.46(1H, m), 4.24(2H, d, J=7.4 Hz), 7.41 (1H, t, J=7.4Hz), 7.49 (2H, dd, J=7.4, 7.4 Hz), 7.65 (2H, d, J=7.0 Hz), 7.74(2H, d,J=8.4 Hz), 7.95(2H, d, J=8.4 Hz), 8.73(1H, s), 14.22(1H, s). IR(KBr)cm⁻¹: 2963, 1749, 1631, 1565, 1470, 735.

6) Preparation of6-(4-biphenylyl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),6-(4-biphenylyl)-4-carboxy-2-isobutyl-2H-pyridazin-3-one was reacted toyield the title compound as a while solid (yield: 15.6%).

Melting point: 146.4–147.5° C. ¹H NMR(400 MHz, CDCl₃)δ: 1.01(6H, d,J=6.8 Hz), 2.32–2.43(1H, m), 3.13(1H, t, J=6.2 Hz), 4.11(2H, d, J=7.4Hz), 4.74(2H, dd, J=1.2, 6.2 Hz), 7.39(1H, t, J=7.3 Hz), 7.48(2H, dd,J=7.4, 7.4 Hz), 7.64(2H, d, J=7.0 Hz), 7.70(2H, d, J=8.6 Hz), 7.74(1H,t, J=1.2 Hz), 7.90(2H, d, J=8.6 Hz). IR(KBr) cm⁻¹: 3431, 2961, 1647,1596, 1077, 769.

7) Preparation of6-(4-biphenylyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),6-(4-biphenylyl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one wasreacted to yield the title compound as a colorless crystalline powder(yield: 79.3%).

Melting point: 121.3–122.0° C. ¹H NMR(400 MHz, CDCl₃)δ: 1.01 (6H, d,J=6.8 Hz), 2.33–2.42 (1H, m), 3.18 (3H, s), 4.12 (2H, d, J=7.4 Hz),5.30(2H, d, J=1.2 Hz), 7.39(1H, t, J=7.4 Hz), 7.48(2H, dd, J=7.6 Hz),7.64(2H, d, J=7.4 Hz), 7.71(2H, d, J=8.4 Hz), 7.85–7.91(3H, m). IR(KBr)cm⁻¹: 2964, 1658, 1610, 1354, 1165, 874, 529.

8) Preparation of6-(4-biphenylyl)-4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(4-biphenylyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand tert-butyl 1-pipeazinecarboxylate were reacted to yield the titlecompound as a yellow oil (yield: 87.7%).

¹H NMR(400 MHz, CDCl₃)δ: 1.00(6H, d, J=6.6 Hz), 1.47(9H, s),2.30–2.43(1H, m), 2.54(4H, t, J=4.9 Hz), 3.51(4H, t, J=4.9 Hz), 3.60(2H,d, J=1.4 Hz), 4.10(2H, d, J=7.4 Hz), 7.38(1H, tt, J=1.4, 7.2 Hz),7.47(2H, dd, J=7.4, 7.4 Hz), 7.64(2H, d, J=7.0 Hz), 7.70(2H, d, J=8.6Hz), 7.85–7.92(3H, m).

Example 67 Preparation of6-(4-biphenylyl)-2-isobutyl-4-(1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 2,6-(4-biphenylyl)-4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 51.5%).

Melting point: 226.8–228.0° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.97(6H, d,J=6.8 Hz), 2.25–2.36(1H, m), 3.19(4H, br), 3.34(4H, t, J=5.1 Hz),3.98(2H, s), 4.05(2H, d, J=7.1 Hz), 7.39(1H, t, J=7.3 Hz), 7.49(2H, dd,J=7.7, 7.7 Hz), 7.71(2H, d, J=7.8 Hz), 7.79(2H, d, J=8.3 Hz), 7.99(2H,d, J=8.3 Hz), 8.29(1H, s). IR(KBr) cm⁻¹: 1653, 1604, 1446, 771. Massm/z: 402(M⁺)

Example 68 Preparation of6-(4-biphenylyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(4-biphenylyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as ayellow oil (yield: 68.2%).

¹H NMR(400 MHz, CDCl₃)δ: 1.00(6H, d, J=6.6 Hz), 2.30–2.43(1H, m),2.34(3H, s), 2.55(4H, br), 2.65(4H, br), 3.61(2H, d, J=1.2 Hz), 4.10(2H,d, J=7.2 Hz), 7.38(1H, t, J=7.3 Hz), 7.47(2H, dd, J=7.5, 7.5 Hz),7.64(2H, d, J=7.2 Hz), 7.70(2H, d, J=8.4 Hz), 7.84(1H, s), 7.90(2H, d,J=8.4 Hz).

Example 69 Preparation of6-(4-biphenylyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,6-(4-biphenylyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 69.9%).

Melting point: 262.2–263.6° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.97(6H, d,J=6.6 Hz), 2.26–2.35(1H, m), 2.77(3H, s), 3.10(4H, br), 3.34(4H, br),3.85(2H, s), 4.04(2H, d, J=7.1 Hz), 7.39(1H, t, J=7.6 Hz), 7.49(2H, dd,J=8.0, 8.0 Hz), 7.71(2H, d, J=8.0 Hz), 7.78(2H, d, J=8.3 Hz), 7.89(2H,d, J=8.3 Hz), 8.13(1H, s). IR(KBr) cm⁻¹: 1652, 1607, 1465, 1050. Massm/z: 416(M⁺)

Example 70 Preparation of6-(4-biphenylyl)-4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(4-biphenylyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as a yellowoil (yield: 62.4%).

¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d, J=6.6 Hz), 2.30–2.43(1H, m),2.73(4H, t, J=4.8 Hz), 3.67(4H, t, J=4.8 Hz), 3.73(2H, s), 4.12(2H, d,J=7.4 Hz), 7.38(1H, t, J=7.2 Hz), 7.47(2H, dd, J=7.2, 7.2 Hz), 7.63(2H,d, J=7.4 Hz), 7.68(2H, d, J=8.2 Hz), 7.79(1H, s), 7.89(2H, d, J=8.2 Hz).

Example 71 Preparation of6-(4-biphenylyl)-4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,6-(4-biphenylyl)-4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 63.9%).

Melting point: 218.3–218.6° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.98(6H, d,J=6.8 Hz), 2.26–2.37(1H, m), 3.36(4H, t, J=5.1 Hz), 3.85(4H, t, J=5.1Hz), 4.08 (2H, d, J=7.3 Hz), 4.48 (2H, s), 7.40(1H, tt, J=1.2, 7.3 Hz),7.49(2H, dd, J=7.3 Hz), 7.72(2H, dd, J=1.2, 7.3 Hz), 7.81(2H, d, J=8.3Hz), 8.01(2H, d, J=8.3 Hz), 8.52(1H, s). IR(KBr) cm⁻¹: 1654, 1607, 1053,847, 769. m/z(EI): 403(M⁺—H₂O)

Example 72 Preparation of6-(4-biphenylyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 7,6-(4-biphenylyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 87.7%).

¹H NMR(400 MHz, CDCl₃)δ: 1.00(6H, d, J=6.6 Hz), 2.36(6H, s),2.29–2.43(1H, m), 3.52(2H, d, J=1.0 Hz), 4.10(2H, d, J=7.2 Hz), 7.37(1H,t, J=7.4 Hz), 7.46(2H, dd, J=7.4, 7.4 Hz), 7.63(2H, d, J=7.2 Hz),7.68(2H, d, J=8.4 Hz), 7.85(1H, s), 7.92(2H, d, J=8.4 Hz).

Example 73 Preparation of6-(4-biphenylyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,6-(4-biphenylyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-one wasreacted to yield the title compound as colorless flakes (yield: 58.2%).

Melting point: 243.9–244.1° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.98(6H, d,J=6.6 Hz), 2.26–2.37(1H, m), 2.83(6H, s), 4.03(2H, d, J=7.1 Hz),4.30(2H, s), 7.39(1H, tt, J=1.2, 7.3 Hz), 7.49(2H, dd, J=7.3, 7.3 Hz),7.72(2H, dd, J=1.2, 7.1 Hz), 7.81(2H, d, J=8.8 Hz), 8.02(2H, d, J=8.6Hz), 8.57(1H, s). IR(KBr) cm⁻¹: 1647, 1604, 1460, 1409, 1052. Mass m/z:361(M⁺)

Example 74 Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(3-chloro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand tert-butyl 1-piperazinecarboxylate were reacted to yield the titlecompound as a yellow oil (yield: 89.0%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.8 Hz), 1.47(9H, s),2.27–2.40(1H, m), 2.52(4H, t, J=4.9 Hz), 3.50(4H, t, J=5.0 Hz), 3.57(2H,d, J=1.4 Hz), 3.96(3H, s), 4.07(2H, d, J=7.2 Hz), 7.00(1H, d, J=8.6 Hz),7.66(1H, dd, J=2.4, 8.6 Hz), 7.74(1H, t, J=1.3 Hz), 7.86(1H, d, J=2.4Hz).

Example 75 Preparation of6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-(1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 2,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(3-chloro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as a white solid (yield: 70.2%).

Melting point: 203.6–204.5° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.95(6H, d,J=6.6 Hz), 2.20–2.34(1H, m), 3.14(4H, br), 3.31(4H, t, J=5.2 Hz),3.93(5H, s), 4.01(2H, d, J=7.0 Hz), 7.26(1H, d, J=8.8 Hz), 7.84(1H, dd,J=2.4, 8.6 Hz), 7.91(1H, d, J=2.4 Hz), 8.19(1H, s). IR(KBr) cm⁻¹: 1654,1608, 1507, 1289, 1065. Mass m/z: 390(M⁺), 392(M⁺).

Example 76 Preparation of6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as ayellow oil (yield: 76.1%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.6 Hz), 2.28–2.40 (1H, m),2.33(3H, s), 2.53(4H, br), 2.63(4H, br), 3.58(2H, d, J=1.2 Hz), 3.96(3H,s), 4.06(2H, d, J=7.2 Hz), 7.01 (1H, d, J=8.6 Hz), 7.67(1H, dd, J=2.2,8.6 Hz), 7.72(1H, s), 7.86(1H, d, J=2.2 Hz).

Example 77 Preparation of6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 67.5%).

Melting point: 235.8–236.7° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.94(6H, d,J=6.6 Hz), 2.25–2.32(1H, m), 2.77(3H, s), 3.15(4H, br), 3.36(4H, br),3.88(2H, s), 3.93(3H, s), 4.01(2H, d, J=7.0 Hz), 7.26(1H, d, J=8.6 Hz),7.83(1H, dd, J=2.2, 8.6 Hz), 7.91(1H, d, J=2.2 Hz), 8.12(1H, s). IR(KBr)cm⁻¹: 1653, 1608, 1507, 1289, 1064. Mass m/z: 404(M⁺), 406(M⁺).

Example 78 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-chloro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as a yellowoil (yield: 79.6%).

¹H NMR(400 MHz, CDCl₃)δ: 0.96(6H, d, J=6.6 Hz), 2.28–2.39(1H, m),2.71(4H, t, J=4.9 Hz), 3.66(4H, t, J=4.9 Hz), 3.70(2H, s), 3.94(3H, s),4.07(2H, d, J=7.4 Hz), 6.98(1H, d, J=8.8 Hz), 7.68(1H, dd, J=1.8, 8.7Hz), 7.72(1H, s), 7.85(1H, d, J=2.1 Hz).

Example 79 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-chloro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-chloro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 60.1%).

Melting point: 153.0–153.5° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.95(6H, d,J=6.6 Hz), 2.23–2.34(1H, m), 3.34(4H, t, J=5.1 Hz), 3.83(4H, t, J=5.1Hz), 3.94(3H, s), 4.04(2H, d, J=7.1 Hz), 4.44(2H, s), 7.28(1H, d, J=8.8Hz), 7.85(1H, dd, J=2.4, 8.6 Hz), 7.94(1H, d, J=2.4 Hz), 8.45(1H, s).IR(KBr) cm⁻¹: 1652, 1607, 1508, 1421, 1293, 1062. Mass m/z: 391(M⁺—H₂O)

Example 80 Preparation of6-(3-chloro-4-methoxyphenyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 7,6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 84.8%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.6 Hz), 2.31–2.39(1H, m),2.35(6H, s), 3.50(2H, s), 3.95(3H, s), 4.07(2H, d, J=7.2 Hz), 6.99(1H,d, J=8.6 Hz), 7.70(1H, dd, J=1.4, 8.6 Hz), 7.88(1H, d, J=1.4 Hz).

Example 81 Preparation of6-(3-chloro-4-methoxyphenyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,6-(3-chloro-4-methoxyphenyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as a white solid (yield: 69.4%).

Melting point: 213.6–214.3° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.95(6H, d,J=6.8 Hz), 2.22–2.34(1H, m), 2.81(6H, s), 3.94(3H, s), 4.04(2H, d, J=7.1Hz), 4.27(2H, s), 7.28(1H, d, J=8.8 Hz), 7.87(1H, dd, J=2.2, 8.8 Hz),7.95(1H, d, J=2.2 Hz), 8.53(1H, s). IR(KBr) cm⁻¹: 1652, 1608, 1508,1289, 1064. Mass m/z: 349(M⁺), 351(M⁺).

Example 82 Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one 1)Preparation of ethyl2-ethoxycarbonyl-4-(4-fluoro-3-methylphenyl)-2-hydroxy-4-oxobutanoate

Following the procedure of Example 1(3), 5-acetyl-2-fluorotoluene wasreacted to yield the title compound as pale yellow prisms (yield:95.9%).

¹H NMR(400 MHz, CDCl₃)δ: 1.30(6H, t, J=7.1 Hz), 2.33(3H, d, J=1.7 Hz),3.79(2H, s), 4.29(1H, s), 4.31(4H, q, J=7.1 Hz), 7.08(1H, dd, J=8.8, 8.8Hz), 7.78–7.85(2H, m).

2) Preparation of4-carboxy-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(4), ethyl2-ethoxycarbonyl-4-(4-fluoro-3-methylphenyl)-2-hydroxy-4-oxobutanoatewas reacted to yield the title compound as a pale yellow crystallinepowder (yield: 88.9%).

Melting point: 213.6–214.3° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 2.51(3H, d,J=1.7 Hz), 7.26(1H, dd, J=9.1, 9.1 Hz), 7.77–7.81(1H, m), 7.89(1H, d,J=7.3 Hz), 8.49(1H, s), 13.99(1H, br).

3) Preparation of6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of Example 1(5),4-carboxy-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one was reacted toyield the title compound as a pale yellow crystalline powder (yield:76.8%).

¹H NMR(400 MHz, CDCl₃)δ: 2.35(3H, d, J=2.0 Hz), 3.99(3H, s), 7.10(1H,dd, J=8.9, 8.9 Hz), 7.58–7.62(1H, m), 7.60(1H, d, J=7.3 Hz), 8.31(1H,s).

4) Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(4-fluoro-3-methylphenyl)-2-methoxycarbonyl-2H-pyridazin-3-one wasreacted to yield the title compound as pale yellow prisms (yield:86.3%).

Melting point: 71.4–73.8° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d, J=6.8Hz), 2.31–2.42(1H, m), 2.35(3H, d, J=2.0 Hz), 3.98(3H, s), 4.12(2H, d,J=7.3 Hz), 7.10(1H, dd, J=8.8, 8.8 Hz), 7.57–7.65(2H, m), 8.21(1H, s).

5) Preparation of4-carboxy-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 1(7),6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow needles (yield:90.0%).

Melting point: 129.3–132.1° C. ¹H NMR(400 MHz, CDCl₃)δ: 1.02(6H, d,J=6.8 Hz), 2.33–2.44(1H, m), 2.37(3H, d, J=2.0 Hz), 4.21(2H, d, J=7.3Hz), 7.13(1H, dd, J=8.8, 8.8 Hz), 7.64–7.71(2H, m), 8.63(1H, s). IR(KBr)cm⁻¹: 1742, 1636, 1537, 1422. Mass m/z: 304(M⁺).

6) Preparation of6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one wasreacted to yield the title compound as colorless needles (yield: 24.7%).

Melting point: 107.4–110.4° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d,J=6.6 Hz), 2.29–2.40(1H, m), 2.35(3H, d, J=1.7 Hz), 3.14(1H, t, J=5.9Hz), 4.08(2H, d, J=7.6 Hz), 4.71(2H, d, J=5.9 Hz), 7.08 (1H, dd, J=8.8,8.8 Hz), 7.56–7.65(3H, m). IR(KBr) cm⁻¹: 3401, 1658, 1648, 1618, 1602,1501. Mass m/z: 290(M⁺).

7) Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless needles (yield:91.4%).

Melting point: 114.6–117.1° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d,J=6.8 Hz), 2.29–2.40(1H, m), 2.36(3H, s), 3.17(3H, s), 4.08(2H, d, J=7.6Hz), 5.27(2H, d, J=1.5 Hz), 7.09 (1H, dd, J=8.9, 8.9 Hz), 7.56–7.69(2H,m), 7.75(1H, t, J=1.5 Hz). IR(KBr) cm⁻¹: 1656, 1611, 1505, 1354, 1166.Mass m/z: 368(M⁺).

8) Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as aslightly yellow oil (yield: 79.1%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.8 Hz), 2.27–2.40(1H, m),2.32(3H, s), 2.36(3H, d, J=2.0 Hz), 2.51(4H, br), 2.62(4H, br), 3.58(2H,d, J=1.5 Hz), 4.07(2H, d, J=7.3 Hz), 7.09 (1H, dd, J=8.8, 8.8 Hz),7.58(1H, ddd, J=2.0, 4.9, 8.8 Hz), 7.64(1H, dd, J=2.0, 7.3 Hz), 7.73(1H,t, J=1.5 Hz). IR(Neat) cm⁻¹: 1652, 1609, 1503. Mass m/z: 372(M⁺).

Example 83 Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless prisms (yield:95.9%).

Melting point: 234.8–237.4° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:0.93(6H, d, J=6.8 Hz), 2.19–2.30(1H, m), 2.32(3H, d, J=2.0 Hz), 2.81(3H,s), 2.89–3.62(10H, brm), 4.00(2H, d, J=7.3 Hz), 7.29(1H, dd, J=9.0, 9.0Hz), 7.72–7.78(1H, m), 7.83(1H, dd, J=2.4, 7.6 Hz), 8.31(1H, brs).IR(KBr) cm⁻¹: 1660, 1609, 1504.

Example 84 Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methylaminomethyl-2H-pyridazin-3-one

Following the procedure of Example 9(4),6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow oil (yield:96.2%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.8 Hz), 1.65(1H, br),2.29–2.42(1H, m), 2.34(3H, d, J=1.7 Hz), 2.51(3H, s), 3.77(2H, d, J=1.2Hz), 4.07(2H, d, J=7.3 Hz), 7.07(1H, dd, J=8.8, 8.8 Hz), 7.54–7.63(2H,m), 7.64(1H, t, J=1.2 Hz). IR(Neat) cm⁻¹: 3306, 1653, 1605, 1507. Massm/z: 303(M⁺).

Example 85 Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methylaminomethyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methylaminomethyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless prisms (yield:86.6%).

Melting point: 196.8–199.7° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.93(6H, d,J=6.8 Hz), 2.19–2.31(1H, m), 2.32(3H, s), 2.65(3H, s), 4.02(2H, d, J=7.3Hz), 4.12(2H, s), 7.31(1H, dd, J=8.5, 8.5 Hz), 7.72–7.78(1H, m),7.80–7.85(1H, m), 8.32(1H, s). IR(KBr) cm⁻¹: 2722, 1652, 1615, 1505.

Example 86 Preparation of4-(4-benzyl-1-piperazinyl)methyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand 1-benzylpiperazine were reacted to yield the title compound as apale yellow oil (yield: 98.6%).

¹H NMR(400 MHz, CDCl₃)δ: 0.97(6H, d, J=6.8 Hz), 2.29–2.39 (1H, m),2.36(3H, d, J=1.7 Hz), 2.55(4H, br), 2.61(4H, br), 3.55(2H, s), 3.57(2H,d, J=1.2 Hz), 4.06(2H, d, J=7.6 Hz), 7.09(1H, dd, J=8.9, 8.9 Hz),7.23–7.34 (5H, m), 7.51 (1H, ddd, J=2.4, 4.8, 8.9 Hz), 7.63(1H, dd,J=2.4, 7.2 Hz), 7.72(1H, s). IR(Neat) cm⁻¹: 1652, 1608, 1505. Mass m/z:448(M⁺).

Example 87 Preparation of4-(4-benzyl-1-piperazinyl)methyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,4-(4-benzyl-1-piperazinyl)methyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless needles (yield:95.3%).

Melting point: 259.1–263.1° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:0.93(6H, d, J=6.6 Hz), 2.17–2.29(1H, m), 2.32(3H, s), 2.55(4H, br),3.23–3.56(8H, brm), 4.00(2H, d, J=7.3 Hz), 4.11(2H, brs), 4.38(2H, brs),7.29(1H, dd, J=9.0, 9.0 Hz), 7.43–7.48(3H, m), 7.59–7.65(2H, m),7.72–7.77(1H, m), 7.79–7.84(1H, m), 8.35(1H, brs). IR(KBr) cm⁻¹: 1660,1618, 1612, 1453.

Example 88 Preparation of4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 7,6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a slightly yellow oil (yield:96.4%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.8 Hz), 2.28–2.39(1H, m),2.35(3H, d, J=2.2 Hz), 2.56(6H, s), 3.50(2H, d, J=1.2 Hz), 4.07(2H, d,J=7.3 Hz), 7.07(1H, dd, J=8.9, 8.9 Hz), 7.59–7.67(2H, m), 7.74(1H, t,J=1.2 Hz). IR(Neat) cm⁻¹: 1652, 1608, 1506. Mass m/z: 317(M⁺).

Example 89 Preparation of4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless needles (yield:97.2%).

Melting point: 208.5–213.0° C. ¹H NMR(400 MHz, DMSO-d₅)δ: 0.94(6H, d,J=6.6 Hz), 2.19–2.30(1H, m), 2.32(3H, s), 2.81(6H, s), 4.03(2H, d, J=7.0Hz), 4.30(2H, s), 7.30(1H, dd, J=9.0, 9.0 Hz), 7.74–7.80(1H, m),7.85(1H, m), 8.51(1H, s). IR(KBr) cm⁻¹: 1648, 1608, 1507.

Example 90 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as aslightly yellow oil (yield: 91.5%).

¹H NMR(400 MHz, CDCl₃)δ: 0.97(6H, d, J=6.8 Hz), 2.27–2.40(1H, m),2.34(3H, d, J=2.0 Hz), 2.70(4H, t, J=5.0 Hz), 3.66(4H, d, J=5.0 Hz),3.69(2H, s), 3.91(2H, br), 4.07(2H, d, J=7.6 Hz), 7.07(1H, dd, J=8.9,8.9 Hz), 7.60(1H, ddd, J=2.2, 5.1, 8.9 Hz), 7.64(1H, dd, J=2.2, 7.3 Hz),7.71(1H, s). IR(Neat) cm⁻¹: 3391, 1654, 1371, 1505. Mass m/z:359(M⁺—H₂O).

Example 91 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow needles(yield: 92.4%).

Melting point: 155.1–157.3° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.94(6H, d,J=6.6 Hz), 2.20–2.31(1H, m), 2.32(3H, d, J=1.2 Hz), 3.35(4H, br,overlapped with H₂O), 3.82(4H, br), 4.02(2H, d, J=7.3 Hz), 4.50(2H, s),5.37(2H, br), 7.30(1H, dd, J=9.0, 9.0 Hz), 7.78(1H, ddd, J=2.0, 4.9, 9.0Hz), 7.85(1H, dd, J=2.0, 7.3 Hz), 7.71(1H, s). IR(KBr) cm⁻¹: 3281, 1655,1606.

Example 92 Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(piperidino)methyl-2H-pyridazin-3-one

6-(4-Fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one(80 mg, 0.22 mmol) and piperidine (55 mg, 0.65 mmol) were dissolved inethanol (0.5 mL), and the mixture was heated at 80° C. for 1 hour understirring. The solvent was distilled off under reduced pressure. Theresidue was purified by preparative thin-layer chromatography on silicagel [developing solvent: chloroform/methanol (10/1)] to yield the titlecompound as a slightly yellow oil (73 mg, 94.0%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.9 Hz), 1.45–1.53(2H, m),1.61–1.68(4H, m), 2.28–2.41(1H, m), 2.36(3H, d, J=2.0 Hz), 2.47–2.53(4H,m), 3.52(2H, d, J=1.5 Hz), 4.07(2H, d, J=7.3 Hz), 7.08(1H, dd, J=8.9,8.9 Hz), 7.59(1H, ddd, J=1.7, 4.9, 8.9 Hz), 7.65(1H, dd, J=1.7, 7.3 Hz),7.76(1H, t, J=1.5 Hz). IR(Neat) cm⁻¹: 1652, 1616, 1506. Mass m/z:357(M⁺).

Example 93 Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(piperidino)methyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(piperidino)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow prisms(yield: 90.7%).

¹H NMR(400 MHz, DMSO-d₆)δ: 0.94(6H, d, J=6.6 Hz), 1.34–1.47(1H, m),1.64–1.73(1H, m), 1.74–1.83(4H, m), 2.20–2.30(1H, m), 2.32(3H, s),2.95–3.02(2H, m), 3.36–3.45(1H, m), 4.02(2H, d, J=7.3 Hz), 4.25(2H, d,J=5.1 Hz), 7.30(1H, dd, J=9.0, 9.0 Hz), 7.75–7.80(1H, m), 7.83–7.87(1H,m), 8.59(1H, s). IR(KBr) cm⁻¹: 2532, 1652, 1616, 1505, 1433.

Example 94 Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(morpholino)methyl-2H-pyridazin-3-one

Following the procedure of Example 92,6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand morpholine were reacted to yield the title compound as a slightlyyellow oil (yield: 97.4%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.8 Hz), 2.28–2.41(1H, m),2.36(3H, d, J=2.0 Hz), 2.58(4H, t, J=4.6 Hz), 3.57(2H, d, J=1.2 Hz),3.78(4H, t, J=4.6 Hz), 4.07(2H, d, J=7.3 Hz), 7.09(1H, dd, J=8.8, 8.8Hz), 7.58(1H, ddd, J=2.0, 4.9, 8.8 Hz), 7.64(1H, dd, J=2.0, 7.3 Hz),7.75(1H, t, J=1.5 Hz). IR(Neat) cm⁻¹: 1659, 1606, 1503. Mass m/z:359(M⁺).

Example 95 Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(morpholino)methyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(morpholino)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless prisms (yield:92.4%).

Melting point: 215.4–216.6° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.94(6H, d,J=6.6 Hz), 2.19–2.30(1H, m), 2.32(3H, s), 3.21(2H, br), 3.79–3.98(6H,m), 4.02(2H, d, J=7.3 Hz), 4.33(2H, brs), 7.30(1H, dd, J=9.0, 9.0 Hz),7.74–7.79(1H, m), 7.81–7.86(1H, m), 8.56(1H, brs). IR(KBr) cm⁻¹: 2392,1647, 1607.

Example 96 Preparation of4-aminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one 1)Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-phthalimidomethyl-2H-pyridazin-3-one

Following the procedure of Example 24(1),6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow needles(yield: 93.7%).

Melting point: 181.2–187.2° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d,J=6.6 Hz), 2.29–2.40(1H, m), 2.30(3H, s), 4.07(2H, d, J=7.3 Hz), 4.91(2H, s), 7.01(1H, dd, J=9.0, 9.0 Hz), 7.31(1H, s), 7.41–7.46(1H, m),7.50–7.53(1H, m), 7.76–7.81(2H, m), 7.90–7.95(2H, m). IR(KBr) cm⁻¹:1720, 1656, 1619, 1611. Mass m/z: 419(M⁺).

2) Preparation of4-aminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 24(2),6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-phthalimidomethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a slightly yellow oil (yield:99.6%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.8 Hz), 1.64(2H, br),2.30–2.40(1H, m), 2.35(3H, d, J=2.0 Hz), 3.89(2H, d, J=1.2 Hz), 4.07(2H,d, J=7.3 Hz), 7.07(1H, dd, J=8.8, 8.8 Hz), 7.60(1H, ddd, J=2.1, 4.9, 8.8Hz), 7.64(1H, dd, J=2.1, 7.4 Hz), 7.67(1H, t, J=1.2 Hz). IR(Neat) cm⁻¹:3372, 3301, 1655, 1605, 1504. Mass m/z: 289(M⁺).

Example 97 Preparation of4-aminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-aminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless needles (yield:79.8%).

Melting point: 217.5–220.5° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:0.93(6H, d, J=6.6 Hz), 2.20–2.30(1H, m), 2.32(3H, d, J=1.7 Hz), 4.01(2H,d, J=2.2 Hz), 4.02(2H, d, J=7.3 Hz), 7.31(1H, dd, J=9.0, 9.0 Hz),7.75(1H, ddd, J=2.1, 4.9, 9.0 Hz), 7.83(1H, dd, J=2.1, 7.4 Hz), 8.28(1H,s). IR(KBr) cm⁻¹: 2960, 2927, 2872, 1656, 1614, 1507.

Example 98 Preparation of4-diethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 9(4),6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand diethylamine were reacted to yield the title compound as a slightlyyellow oil (yield: 94.7%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.8 Hz), 1.07(6H, t, J=7.1 Hz),2.30–2.41(1H, m), 2.35(3H, d, J=1.5 Hz), 2.61(4H, q, J=7.1 Hz), 3.60(2H,d, J=1.7 Hz), 4.08(2H, d, J=7.5 Hz), 7.08(1H, dd, J=8.9, 8.9 Hz),7.60(1H, ddd, J=2.2, 4.9, 8.9 Hz), 7.65(1H, dd, J=2.2, 7.3 Hz), 7.85(1H,t, J=1.5 Hz). IR(Neat) cm⁻¹: 1652, 1609, 1506. Mass m/z: 345(M⁺).

Example 99 Preparation of4-diethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-diethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow needles(yield: 70.1%).

Melting point: 154.3–157.3° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.92(6H, d,J=6.8 Hz), 1.29(6H, t, J=7.2 Hz), 2.20–2.30(1H, m), 2.32(3H, d, J=1.2Hz), 3.09–3.25(4H, m), 4.03(2H, d, J=7.3 Hz), 4.28(2H, d, J=5.6 Hz),7.30(1H, dd, J=9.0, 9.0 Hz), 7.80(1H, ddd, J=2.0, 4.9, 9.0 Hz), 7.87(1H,dd, J=2.0, 7.3 Hz), 7.85(1H, t, J=1.5 Hz). IR(KBr) cm⁻¹: 2559, 2491,1652, 1613, 1507.

Example 100 Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand tert-butyl 1-piperazinecarboxylate were reacted to yield the titlecompound as a slightly yellow oil (yield: 97.5%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.6 Hz), 1.46(9H, s),2.28–2.40(1H, m), 2.36(3H, d, J=1.7 Hz), 3.50 (4H, t, J=4.9 Hz), 3.58(2H, d, J=1.0 Hz), 4.08(2H, d, J=7.3 Hz), 7.09(1H, dd, J=8.9, 8.9 Hz),7.58(1H, ddd, J=2.0, 4.9, 8.9 Hz), 7.63(1H, dd, J=2.0, 7.3 Hz), 7.75(1H,s). IR(Neat) cm⁻¹: 1695, 1652, 1608, 1506.

Example 101 Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 20,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow oil (yield:quantitative).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.8 Hz), 1.47(1H, br),2.28–2.40(1H, m), 2.36(3H, d, J=1.7 Hz), 2.56(4H, t, J=4.9 Hz), 2.97(4H,t, J=4.9 Hz), 3.56(2H, d, J=1.4 Hz), 4.07(2H, d, J=7.3 Hz), 7.09(1H, dd,J=8.8, 8.8 Hz), 7.58(1H, ddd, J=2.0, 4.9, 8.8 Hz), 7.64(1H, dd, J=2.0,7.3 Hz), 7.75(1H, t, J=1.4 Hz). IR(Neat) cm⁻¹: 3308, 1648, 1607, 1506.Mass m/z: 358(M⁺).

Example 102 Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow prisms (yield:87.2%).

Melting point: 154.9–158.0° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.94(6H, d,J=6.8 Hz), 2.19–2.30(1H, m), 2.32(3H, d, J=1.7 Hz), 3.04(4H, br),3.71(4H, br), 4.01(2H, d, J=7.3 Hz), 7.28(1H, dd, J=8.8, 8.8 Hz),7.76(1H, ddd, J=2.0, 4.9, 8.8 Hz), 7.83(1H, dd, J=2.0, 7.3 Hz), 8.40(1H,brs). IR(KBr) cm⁻¹: 1659, 1610, 1504, 1422.

Example 103 Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(3,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one 1)Preparation of ethyl4-(3,4-difluorophenyl)-2-ethoxycarbonyl-2-hydroxy-4-oxobutanoate

Following the procedure of Example 1(3), 3′,4′-difluoroacetophenone wasreacted to yield the title compound as a pale yellow oil (yield: 81.6%).

¹H NMR(400 MHz, CDCl₃)δ: 1.30(6H, t, J=7.1 Hz), 3.78(2H, s), 4.22(1H,s), 4.31(4H, q, J=7.1 Hz), 7.24–7.30(1H, m), 7.73–7.82(2H, m). IR(Neat)cm⁻¹: 3483, 1740, 1695, 1612. Mass m/z: 312(M⁺—H₂O).

2) Preparation of 4-carboxy-6-(3,4-difluorophenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(4), ethyl4-(3,4-difluorophenyl)-2-ethoxycarbonyl-2-hydroxy-4-oxobutanoate wasreacted to yield the title compound as a pale yellow crystalline powder(yield: 88.9%).

3) Preparation of4-methoxycarbonyl-6-(3,4-difluorophenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(5),4-carboxy-6-(3,4-difluorophenyl)-2H-pyridazin-3-one was reacted to yieldthe title compound as a pale yellow crystalline powder (yield: 85.8%).

¹H NMR(400 MHz, CDCl₃)δ: 4.01(3H, s), 7.25–7.32(1H, m), 7.53–7.57(1H,m), 7.67–7.73(1H, m), 8.31(1H, s), 11.70(1H, br). IR(KBr) cm⁻¹: 3223,3159, 1722, 1676, 1659. Mass m/z: 266(M⁺).

4) Preparation of6-(3,4-difluorophenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(3,4-difluorophenyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reactedto yield the title compound as a yellow oil (yield: quantitative).

¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d, J=6.8 Hz), 2.30–2.41(1H, m),3.98(3H, s), 4.13(2H, d, J=7.2 Hz), 7.23–7.30(1H, m), 7.49–7.55(1H, m),7.68(1H, ddd, J=2.2, 7.6, 11.1 Hz), 8.20(1H, s).

5) Preparation of4-carboxy-6-(3,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 1(7),6-(3,4-difluorophenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless fine-needles(yield: 91.4%).

Melting point: 163.4–163.7° C. ¹H NMR(400 MHz, CDCl₃)δ: 1.02(6H, d,J=6.6 Hz), 2.33–2.43(1H, m), 4.22(2H, d, J=7.4 Hz), 7.27–7.35(1H, m),7.56–7.62(1H, m), 7.74(1H, ddd, J=2.4, 7.6, 11.2 Hz), 8.62(1H, s),14.05(1H, s). IR(KBr) cm⁻¹: 3436, 1737, 1635, 1522, 1434, 1276, 1102,806. Mass m/z: 308(M⁺)

6) Preparation of6-(3,4-difluorophenyl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-6-(3,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one wasreacted to yield the title compound as colorless fine-needles (yield:25.0%).

¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d, J=6.8 Hz), 2.29–2.39(1H, m),2.96(1H, t, J=5.9 Hz), 4.08(2H, d, J=7.4 Hz), 4.72(2H, dd, J=1.2, 5.8Hz), 7.22–7.28(1H, m), 7.51–7.55(1H, m), 7.64–7.71(2H, m).

7) Preparation of6-(3,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),6-(3,4-difluorophenyl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one wasreacted to yield the title compound as colorless fine-needles (yield:81.4%).

Melting point: 113.3–113.4° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d,J=6.6 Hz), 2.27–2.40(1H, m), 3.18(3H, s), 4.08(2H, d, J=7.4 Hz),5.28(2H, d, J=1.6 Hz), 7.23–7.30(1H, m), 7.50–7.54(1H, m), 7.68(1H, ddd,J=2.2, 7.6, 11.1 Hz), 7.75(1H, t, J=1.4 Hz). IR(KBr) cm⁻¹: 3447, 1656,1613, 1522, 1354, 1167, 1049, 877. Mass m/z: 372(M⁺)

8) Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(3,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(3,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand tert-butyl 1-piperazinecarboxylate were reacted to yield the titlecompound as a yellow oil (yield: 85.5%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.6 Hz), 1.47(9H, s),2.28–2.38(1H, m), 2.52(4H, t, J=4.7 Hz), 3.51(4H, t, J=4.7 Hz), 3.58(2H,s), 4.07(2H, d, J=7.2 Hz), 7.21–7.29(1H,m), 7.50–7.55(1H,m),7.64–7.71(1H, m), 7.76(1H, d, J=1.0 Hz).

Example 104 Preparation of6-(3,4-difluorophenyl)-2-isobutyl-4-(1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 2,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(3,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as a white solid (yield: 72.5%).

Melting point: 182.5–186.0° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.94(6H, d,J=6.6 Hz), 2.22–2.33(1H,m), 3.11(4H,br), 3.30(4H, t, J=5.1 Hz), 3.90(2H,s), 4.02(2H, d, J=7.1 Hz), 7.52(1H, ddd, J=8.6, 8.6, 10.5 Hz),7.73–7.78(1H, m), 7.90(1H, ddd, J=2.2, 8.0, 11.7 Hz), 8.20(1H, s).IR(KBr) cm⁻¹: 1656, 1609, 1522, 1436, 1276, 1112. Mass m/z: 362(M⁺)

Example 105 Preparation of6-(3,4-difluorophenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(3,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as ayellow oil (yield: 79.1%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.8 Hz), 2.28–2.39(1H, m),2.34(3H, s), 2.55(4H, br), 2.63(4H, br), 3.58(2H, s), 4.07(2H, d, J=7.2Hz), 7.22–7.29(1H,m), 7.50–7.57(1H,m), 7.64–7.72(1H,m), 7.74(1H, s).

Example 106 Preparation of6-(3,4-difluorophenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,6-(3,4-difluorophenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 70.3%).

Melting point: 242.5–243.4° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.94(6H, d,J=6.8 Hz), 2.22–2.33(1H, m), 2.77(3H, s), 3.11(4H, br), 3.34(4H, br),3.84(2H, s), 4.02(2H, d, J=7.1 Hz), 7.52(1H, ddd, J=8.6, 8.6, 10.5 Hz),7.72–7.77(1H, m), 7.89(1H, ddd, J=2.2, 7.9, 11.7 Hz), 8.12(1H, s).IR(KBr) cm⁻¹: 1652, 1607, 1522, 1435, 1278. Mass m/z: 376(M⁺)

Example 107 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(3,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as a yellowoil (yield: 75.8%).

¹H NMR(400 MHz, CDCl₃)δ: 0.97(6H, d, J=6.6 Hz), 2.25–2.38(1H, m),2.70(4H, br), 3.64–3.70(6H, m), 4.06(2H, d, J=7.4 Hz), 7.15–7.25(1H, m),7.54–7.58(1H, m), 7.67–7.73(1H, m), 7.88(1H, s).

Example 108 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3,4-difluorophenyl-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as a white solid (yield: 70.3%).

Melting point: 127.5–128.3° C. ¹H NMR(400 MHz, DMSO₆)δ: 0.95(6H, d,J=6.8 Hz), 2.23–2.34(1H, m), 3.35(4H, t, J=5.1 Hz), 3.84(4H, t, J=5.1Hz), 4.05(2H, d, J=7.1 Hz), 4.45(2H, s), 7.54(1H, ddd, J=8.6, 8.6, 10.5Hz), 7.76–7.81(1H, m), 7.93(1H, ddd, J=2.2, 7.8, 12.0 Hz), 8.53(1H, s).IR(KBr) cm⁻¹: 1653, 1604, 1521, 1437, 1275. Mass m/z: 363(M⁺—H₂O)

Example 109 Preparation of6-(3,4-difluorophenyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 7,6-(3,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 85.5%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.6 Hz), 2.29–2.40(1H, m),2.35(6H, s), 3.50(2H, s), 4.07(2H, d, J=7.4 Hz), 7.20–7.30(1H, m),7.53–7.60(1H, m), 7.67–7.73(1H, m), 7.74(1H, s).

Example 110 Preparation of6-(3,4-difluorophenyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,6-(3,4-difluorophenyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow flakes(yield: 85.9%).

Melting point: 226.5–227.7° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.96(6H, d,J=6.8 Hz), 2.23–2.34(1H, m), 2.81(6H, s), 4.05(2H, d, J=7.1 Hz),4.28(2H, s), 7.54(ddd, J=8.7, 8.7, 10.5 Hz), 7.76–7.81(1H, m), 7.93(1H,ddd, J=2.2, 7.9, 12.0 Hz), 8.57(1H, s). IR(KBr) cm⁻¹: 1648, 1607, 1525,1437, 1288, 1112. Mass m/z: 321(M⁺)

Example 111 Preparation of4-aminomethyl-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one 1)Preparation of ethyl4-(2,4-difluorophenyl)-2-ethoxycarbonyl-2-hydroxy-4-oxobutanoate

Following the procedure of Example 1(3), 2′,4′-difluoroacetophenone wasreacted to yield the title compound as a pale yellow oil (yield: 76.8%).

¹H NMR(400 MHz, CDCl₃)δ: 1.30(6H, t, J=7.1 Hz), 3.81(2H, d, J=3.4 Hz),4.18(1H, s), 4.30(4H, q, J=7.1 Hz), 6.90(1H, ddd, J=2.4, 8.5, 10.0 Hz),6.94–7.00(1H, m), 7.94(1H, ddd, J=6.6, 8.5, 8.5 Hz). IR(Neat) cm⁻¹:3491, 1743, 1692, 1612. Mass m/z: 312(M⁺—H₂O)

2) Preparation of 4-carboxy-6-(2,4-difluorophenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(4), ethyl4-(2,4-difluorophenyl)-2-ethoxycarbonyl-2-hydroxy-4-oxobutanoate wasreacted to yield the title compound as a pale yellow crystalline powder(yield: 95.2%).

3) Preparation of6-(2,4-difluorophenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of Example 1(5),4-carboxy-6-(2,4-difluorophenyl)-2H-pyridazin-3-one was reacted to yieldthe title compound as a pale yellow crystalline powder (yield: 81.2%).

¹H NMR(400 MHz, CDCl₃)δ: 3.99(3H, s), 6.96(1H, ddd, J=2.4, 8.8, 10.1Hz), 6.99–7.04(1H, m), 7.77(1H, ddd, J=6.3, 8.8, 8.8 Hz), 8.30(1H, d,J=2.0 Hz), 12.05(1H, br). IR(KBr) cm⁻¹: 3217, 3148, 1721, 1673, 1611.Mass m/z: 266(M⁺).

4) Preparation of6-(2,4-difluorophenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(2,4-difluorophenyl)-4-methoxycarbonyl-2H-pyridazin-3-on e was reactedto yield the title compound as a pale yellow oil (yield: 84.8%).

¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d, J=6.6 Hz), 2.29–2.42(1H, m),3.97(3H, s), 4.12(2H, d, J=7.3 Hz), 6.94(1H, ddd, J=2.4, 8.8, 11.2 Hz),6.98–7.04(1H, m), 7.73(1H, ddd, J=6.3, 6.3, 8.8 Hz), 8.18(1H, d, J=2.0Hz). IR(Neat) cm⁻¹: 1755, 1748, 1668, 1620, 1506. Mass m/z: 322(M⁺).

5) Preparation of4-carboxy-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 1(7),6-(2,4-difluorophenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow needles(yield: 92.7%).

Melting point: 126.5–128.2° C. ¹H NMR(400 MHz, CDCl₃)δ: 1.02(6H, d,J=6.6 Hz), 2.31–2.43(1H, m), 4.22(2H, d, J=7.6 Hz), 6.96–7.07(2H, m),7.74(1H, ddd, J=6.3, 6.3, 8.8 Hz), 8.61(1H, d, J=2.2 Hz), 14.02(1H, s).IR(KBr) cm⁻¹: 1739, 1636, 1618, 1573, 1465. Mass m/z: 308(M⁺).

6) Preparation of6-(2,4-difluorophenyl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one wasreacted to yield the title compound as a pale yellow oil (yield: 45.0%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.8 Hz), 2.27–2.40(1H, m),3.15(1H, t, J=6.1 Hz), 4.08(2H, d, J=7.3 Hz), 4.69(2H, dd, J=1.2, 6.1Hz), 6.93(1H, ddd, J=2.4, 8.8, 11.2 Hz), 6.96–7.02(1H, m), 7.61–7.63(1H,m), 7.72(1H, ddd, J=6.3, 6.3, 8.8 Hz). IR(Neat) cm⁻¹: 3412, 1652, 1620,1507. Mass m/z: 294(M⁺).

7) Preparation of6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),6-(2,3-difluorophenyl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one wasreacted to yield the title compound as colorless needles (yield: 96.3%).

Melting point: 86.7–88.6° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d, J=6.8Hz), 2.26–2.39(1H, m), 3.16(3H, s), 4.08(2H, d, J=7.3 Hz), 5.26(2H, d,J=1.2 Hz), 6.94(1H, ddd, J=2.4, 8.8, 11.2 Hz), 6.97–7.03(1H, m),7.71(1H, ddd, J=6.3, 6.3, 8.8 Hz), 7.73–7.75(1H, m). IR(KBr) cm⁻¹: 1659,1612, 1508, 1359, 1166. Mass m/z: 372(M⁺).

8) Preparation of6-(2,4-difluorophenyl)-2-isobutyl-4-phthalimidomethyl-2H-pyridazin-3-one

Following the procedure of Example 24(1),6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless needles (yield:91.1%).

Melting point: 152.3–155.6° C. ¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d,J=6.6 Hz), 2.28–2.39(1H, m), 4.07(2H, d, J=7.3 Hz), 4.89(2H, d, J=1.0Hz), 6.83(1H, ddd, J=2.4, 8.8, 11.0 Hz), 6.91–6.97(1H, m), 7.27–7.31(1H,m), 7.66(1H, ddd, J=6.3, 6.3, 8.8 Hz), 7.74–7.80(2H, m), 7.86–7.94(2H,m). IR(KBr) cm⁻¹: 1773, 1720, 1650, 1617, 1509, 1418, 1389. Mass m/z:423(M⁺).

9) Preparation of4-aminomethyl-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 24(2),2-isobutyl-6-(2,4-difluorophenyl)-4-phthalimidomethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a slightly yellow oil (yield:98.4%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.8 Hz), 1.66(2H, br),2.24–2.41(1H, m), 3.87(2H, s), 4.08(2H, d, J=7.3 Hz), 6.92(1H, ddd,J=2.4, 8.8, 11.2 Hz), 6.97–7.02(1H, m), 7.63(1H, t, J=1.1 Hz), 7.71(1H,ddd, J=6.3, 6.3, 8.8 Hz). IR(Neat) cm⁻¹: 3381, 3307, 1652, 1611, 1508.Mass m/z: 293(M⁺).

Example 112 Preparation of4-aminomethyl-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-aminomethyl-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one wasreacted to yield the title compound as slightly yellow needles (yield:94.9%).

Melting point: 161.4–163.9° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.93(6H, d,J=6.8 Hz), 2.18–2.34(1H, m), 4.01(2H, s), 4.02(2H, d, J=7.3 Hz),7.24–7.31(1H, m), 7.46(1H, ddd, J=2.4, 8.8, 11.5 Hz), 7.76(1H, ddd,J=6.3, 6.3, 8.8 Hz), 7.95(1H, s). IR(KBr) cm⁻¹: 1652, 1616, 1597, 1509.

Example 113 Preparation of6-(2,4-difluorophenyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 7,6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a slightly yellow oil (yield:94.1%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.8 Hz), 2.27–2.38(1H, m),2.34(6H, s), 3.49(2H, d, J=1.5 Hz), 4.07(2H, d, J=7.6 Hz), 6.92(1H, ddd,J=2.4, 8.8, 11.2 Hz), 6.95–7.01(1H, m), 7.70(1H, t, J=1.5 Hz), 7.71(1H,ddd, J=6.3, 6.3, 8.8 Hz). IR(Neat) cm⁻¹: 1652, 1612, 1508. Mass m/z:321(M⁺).

Example 114 Preparation of6-(2,4-difluorophenyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,6-(2,4-difluorophenyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow prisms (yield:89.8%).

Melting point: 170.1–173.5° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.94(6H, d,J=6.8 Hz), 2.18–2.29(1H, m), 2.80(6H, s), 4.03(2H, d, J=7.3 Hz),4.30(2H, s), 7.25–7.31(1H, m), 7.45(1H, ddd, J=2.4, 8.8, 11.2 Hz),7.81(1H, ddd, J=6.3, 6.3, 8.8 Hz). 8.15(1H, d, J=1.7 Hz), IR(KBr) cm⁻¹:1648, 1612, 1523, 1510.

Example 115 Preparation of4-diethylaminomethyl-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 9(4),6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand diethylamine were reacted to yield the title compound as a paleyellow oil (yield: quantitative)

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.8 Hz), 1.06(6H, t, J=7.1 Hz),2.27–2.39(1H, m), 2.59(4H, q, J=7.1 Hz), 3.59(2H, d, J=1.7 Hz), 4.07(2H,d, J=7.3 Hz), 6.92 (1H, ddd, J=2.4, 8.8, 11.2 Hz), 6.95–7.01 (1H, m),7.72(1H, ddd, J=6.3, 6.3, 8.8 Hz), 7.83(1H, td, J=1.5, 2.9 Hz). IR(Neat)cm⁻¹: 1656, 1613, 1508. Mass m/z: 349(M⁺).

Example 116 Preparation of4-diethylaminomethyl-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-diethylaminomethyl-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless needles (yield:80.9%).

Melting point: 128.9–131.7° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.94(6H, d,J=6.8 Hz), 1.28(6H, t, J=7.2 Hz), 2.18–2.29(1H, m), 3.10–3.23(4H, m),4.03(2H, d, J=7.3 Hz), 4.29(2H, d, J=5.4 Hz), 7.28(1H, ddd, J=2.2, 8.8,8.8 Hz), 7.45(1H, ddd, J=2.2, 8.8, 8.8 Hz), 7.81(1H, ddd, J=6.3, 8.8,8.8 Hz), 8.24(1H, d, J=1.5 Hz).

Example 117 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as aslightly yellow oil (yield: 97.6%).

¹H NMR(400 MHz, CDCl₃)δ: 0.97(6H, d, J=6.6 Hz), 2.26–2.40(1H, m),2.70(4H, t, J=5.0 Hz), 3.65(4H, t, J=5.0 Hz), 3.70(2H, s), 4.09(2H, d,J=7.3 Hz), 6.92(1H, ddd, J=2.7, 8.8, 11.2 Hz), 6.97–7.03(1H, m),7.63(1H, d, J=2.4 Hz), 7.75(1H, ddd, J=6.3, 6.3, 8.8 Hz). IR(Neat) cm⁻¹:3401, 1648, 1597, 1508. Mass m/z: 363(M⁺—H₂O).

Example 118 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(2,4-difluorophenyl-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow prisms(yield: 89.0%).

Melting point: 161.8–163.9° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.93(6H, d,J=6.6 Hz), 2.18–2.29(1H, m), 3.27–3.40(4H, br, overlapped with H₂O),3.76–3.84(4H, m), 4.03(2H, d, J=7.3 Hz), 4.51(2H, brs), 5.34(2H, br),7.24–7.31(1H, m), 7.41–7.48(1H, m), 7.76–7.84(1H, m), 8.15(1H, m).IR(KBr) cm⁻¹: 3233, 3172, 1645, 1613, 1593, 1421.

Example 119 Preparation of6-(2,4-difluorophenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as apale yellow oil (yield: 94.0%).

¹H NMR(400 MHz, CDCl₃)δ: 0.97(6H, d, J=6.6 Hz), 2.28–2.38(1H,m),2.31(3H, s), 2.50(4H, br), 2.61(4H, br), 3.57(2H, d, J=1.5 Hz),4.07(2H, d, J=7.3 Hz), 6.93(1H, ddd, J=2.4, 8.8, 11.2 Hz), 6.96–7.02(1H,m), 7.69–7.75(2H, m). IR(Neat) cm⁻¹: 1655, 1616, 1596, 1508. Mass m/z:376(M⁺).

Example 120 Preparation of6-(2,4-difluorophenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,6-(2,4-difluorophenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless needles (yield:90.4%).

Melting point: 248.1–251.7° C. (dec.). ¹H NMR(400 MHz, DMSO-d₆, 100°C.)δ: 0.93(6H, d, J=6.8 Hz), 2.20–2.29(1H, m), 2.76(3H, s), 3.09(4H, br,overlapped with H₂O), 3.27(4H, br), 3.74(2H, s), 4.00(2H, d, J=7.1 Hz),7.14–7.29(2H, m), 7.71–7.79(2H, m). IR(KBr) cm⁻¹: 1652, 1612, 1514.

Example 121 Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand tert-butyl 1-piperazinecarboxylate were reacted to yield the titlecompound as a slightly yellow oil (yield: 97.5%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.8 Hz), 1.47(9H, s),2.28–2.39(1H, m), 2.52(4H, t, J=4.9 Hz), 3.49(4H, t, J=4.9 Hz), 3.57(2H,d, J=1.2 Hz), 4.07(2H, d, J=7.3 Hz), 6.93(1H, ddd, J=2.4, 8.8, 11.2 Hz),6.96–7.02(1H, m), 7.69–7.75(2H, m). IR(Neat) cm⁻¹: 1695, 1655, 1613,1508, 1425. Mass m/z: 462(M⁺).

Example 122 Preparation of6-(2,4-difluorophenyl)-2-isobutyl-4-(1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 20,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow oil (yield:quantitative)

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.8 Hz), 1.81(1H, br),2.27–2.39(1H, m), 2.50–2.56(4H, brm), 2.94(4H, t, J=4.8 Hz), 3.54(2H, d,J=1.2 Hz), 4.07(2H, d, J=7.3 Hz), 6.93(1H, ddd, J=2.4, 8.8, 11.2 Hz),6.94–7.02(1H, m), 7.69–7.76(2H, m). IR(Neat) cm⁻¹: 3314, 1655, 1613,1508. Mass m/z: 362(M⁺).

Example 123 Preparation of6-(2,4-difluorophenyl)-2-isobutyl-4-(1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,6-(2,4-difluorophenyl)-2-isobutyl-4-(1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as a slightly yellow crystallinepowder (yield: 90.8%).

Melting point: 136.3–140.9° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.93(6H, d,J=6.6 Hz), 2.20–2.30(1H, m), 2.95(4H, t, J=5.0 Hz), 3.02(4H, t, J=5.0Hz), 3.76(2H, s), 4.00(2H, d, J=7.3 Hz), 7.14–7.20(1H, m), 7.26(1H, ddd,J=2.7, 8.8, 11.2 Hz), 7.86(1H, ddd, J=6.6, 6.6, 8.8 Hz), 7.81(1H, s).IR(KBr) cm⁻¹: 1656, 1616, 1597, 1509, 1426.

Example 124 Preparation of2-benzyl-4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one 1)Preparation of2-benzyl-6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one andbenzyl chloride were reacted to yield the title compound as yellowneedles (yield: 71.0%).

Melting point: 109.0–110.5° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.35(3H, d,J=1.7 Hz), 3.96(3H, s), 5.44(2H, s), 7.10(1H, dd, J=8.8, 8.8 Hz),7.28–7.37(3H, m), 7.52(2H, d, J=6.3 Hz), 7.57–7.64(2H, m), 8.21(1H, s).IR(KBr) cm⁻¹: 1750, 1744, 1657, 1278, 1233, 1123. Mass m/z: 352(M⁺).

2) Preparation of2-benzyl-4-carboxy-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(7),2-benzyl-6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow crystallinepowder (yield: 65.2%).

Melting point: 191.2–192.3° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.37(3H, d,J=2.0 Hz), 5.52(2H, s), 7.13(1H, dd, J=8.8, 8.8 Hz), 7.33–7.41(3H, m),7.48–7.52(2H, m), 7.64–7.70(2H, m), 8.62(1H, s), 14.01(1H, br). IR(KBr)cm⁻¹: 1739, 1633, 1569, 1457, 1423, 1240. Mass m/z: 338(M⁺).

3) Preparation of2-benzyl-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),2-benzyl-4-carboxy-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one wasreacted to yield the title compound as slightly yellow needles (yield:28.4%).

Melting point: 119.5–120.6° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.34(3H, d,J=1.7 Hz), 3.01(1H, t, J=5.9 Hz), 4.70(2H, dd, J=1.2, 5.9 Hz), 5.41(2H,s), 7.08 (1H, dd, J=8.8, 8.8 Hz), 7.27–7.37(3H, m), 7.48(1H, d, J=6.6Hz), 7.57–7.65(2H, m) 7.66(1H, t, J=1.2 Hz). IR(KBr) cm⁻¹: 3330, 1657,1643, 1611, 1597, 1506, 1239. Mass m/z: 324(M⁺).

4) Preparation of2-benzyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-benzyl-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow needles(yield: 98.9%).

Melting point: 147.6–148.3° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.35(3H, d,J=2.0 Hz), 3.15(3H, s), 5.26(2H, d, J=1.2 Hz), 5.41(2H, s), 7.09 (1H,dd, J=8.8, 8.8 Hz), 7.27–7.37(3H, m), 7.47(2H, d, J=6.6 Hz), 7.62(1H, d,J=7.3 Hz), 7.57–7.60(1H, m), 7.75(1H, s). IR(KBr) cm⁻¹: 1656, 1617,1507, 1355, 1168, 1033, 879. Mass m/z: 402(M⁺).

5) Preparation of2-benzyl-4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-benzyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand tert-butyl 1-piperazinecarboxylate were reacted to yield the titlecompound as a yellow oil (yield: 91.8%).

¹H NMR(400 MHz, CDCl₃)δ: 1.46(9H, s), 2.35(3H, d, J=1.8 Hz), 2.50(4H, t,J=4.9 Hz), 3.49(4H, t, J=4.9 Hz), 3.56(2H, d, J=1.4 Hz), 5.40(2H, s),7.26–7.36(4H, m), 7.49(2H, d, J=6.6 Hz), 7.55–7.60(1H, m), 7.63(1H, dd,J=1.8, 7.2 Hz), 7.74(1H, s).

Example 125 Preparation of2-benzyl-6-(4-fluoro-3-methylphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 2,2-benzyl-4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 60.9%).

Melting point: 162.7–180.7° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:2.31(3H, d, J=2.0 Hz), 3.09(4H, br), 3.28(4H, t, J=5.2 Hz), 3.89(2H, s),5.36(2H, s), 7.21–7.40(6H, m), 7.70–7.76(1H, m), 7.79(1H, dd, J=1.7, 7.3Hz), 8.16(1H, s). IR(KBr) cm⁻¹: 1656, 1607, 1505, 1239, 1126, 700. Massm/z: 392(M⁺)

Example 126 Preparation of2-benzyl-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-benzyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as ayellow oil (yield: 81.3%).

¹H NMR(400 MHz, CDCl₃)δ: 2.33(3H, s), 2.36(3H, d, J=1.8 Hz), 2.53(4H,br), 2.61(4H, br), 3.57(2H, d, J=1.4 Hz), 5.40(2H, s), 7.08(1H, t, J=8.9Hz), 7.26–7.36(3H, m), 7.49(2H, d, J=6.8 Hz), 7.56–7.60(1H, m), 7.64(1H,dd, J=1.8, 7.2 Hz), 7.73(1H, s).

Example 127 Preparation of2-benzyl-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-benzyl-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 78.6%).

Melting point: 240.0–242.5° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:2.31(3H, d, J=1.7 Hz), 2.76(3H, s), 3.10(4H, br), 3.33(4H, br), 3.84(2H, s), 5.36 (2H, s), 7.21–7.39 (6H, m), 7.69–7.74 (1H, m), 7.78(1H,dd, J=2.1, 7.8 Hz), 8.09(1H, s). IR(KBr) cm⁻¹: 1653, 1607, 1504, 1454,1240, 1127. Mass m/z: 406(M⁺)

Example 128 Preparation of2-benzyl-4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-benzyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as a yellowoil (yield: 87.6%).

¹H NMR(400 MHz, CDCl₃)δ: 2.33(3H, s), 2.69(4H, t, J=4.9 Hz), 3.64(4H, t,J=5.0 Hz), 3.68(2H, s), 5.40(2H, s), 7.06(1H, t, J=8.9 Hz),7.26–7.38(3H, m), 7.45(2H, d, J=7.0 Hz), 7.58–7.68(2H, m), 7.75(1H, s).

Example 129 Preparation of2-benzyl-4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,2-benzyl-4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow crystallinepowder (yield: 75.9%).

Melting point: 161.7–163.0° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 2.31(2H, d,J=2.0 Hz), 3.34(4H, t, J=5.2 Hz), 3.83(4H, t, J=5.4 Hz), 4.47(2H, s),5.39(2H, s), 7.23–7.40(6H, m), 7.73–7.77(1H, m), 7.82(1H, dd, J=1.7, 7.3Hz), 8.47(1H, s). IR(KBr) cm⁻¹: 1602, 1503, 1239, 1088. Mass m/z:393(M⁺—H₂O)

Example 130 Preparation of2-benzyl-4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 7,2-benzyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand dimethylamine were reacted to yield the title compound as a yellowoil (yield: 92.7%).

¹H NMR(400 MHz, CDCl₃)δ: 2.34(9H, s), 3.49(2H, s), 5.40(2H, s), 7.06(1H,t, J=8.9 Hz), 7.25–7.35(3H, m), 7.49(2H, d, J=7.4 Hz), 7.58–7.67(2H, m),7.75(1H, s).

Example 131 Preparation of2-benzyl-4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,2-benzyl-4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as colorless flakes (yield:72.6%).

Melting point: 225.3–226.0° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 2.31(3H, d,J=2.0 Hz), 2.81(6H, s), 4.28(2H, s), 5.39(2H, s), 7.21–7.41(6H, m),7.73–7.78(1H, m), 7.83(1H, dd, J=2.2, 7.6 Hz), 8.52(1H, s). IR(KBr)cm⁻¹: 1652, 1610, 1506, 1240, 1126, 702. Mass m/z: 351(M⁺)

Example 132 Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-cinnamyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one 1)Preparation of2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(3-fluoro-4-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one andcinnamyl bromide were reacted to yield the title compound as pale yellowneedles (yield: 58.7%).

Melting point: 95.9–96.7° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.35(3H, d, J=1.7Hz), 3.99(3H, s), 5.04(2H, dd, J=1.2, 6.8 Hz), 6.45(1H, dt, J=15.9, 6.8Hz), 6.75(1H, d, J=15.9 Hz), 7.10(1H, dd, J=8.9, 8.9 Hz), 7.20–7.33(3H,m), 7.39(2H, d, J=7.1 Hz), 7.58–7.66(2H, m), 8.23(1H, s). IR(KBr) cm⁻¹:1724, 1661, 1603, 1501, 1292, 1234, 1123. Mass m/z: 378(M⁺).

2) Preparation of4-carboxy-2-cinnamyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(7),2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow needles (yield:85.1%).

Melting point: 142.8–143.6° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.36(3H, d,J=2.0 Hz), 5.12(2H, dd, J=1.2, 6.8 Hz), 6.42(1H, dt, J=15.9, 6.8 Hz),6.80(1H, d, J=15.9 Hz), 7.13(1H, dd, J=8.8, 8.8 Hz), 7.22–7.36(3H, m),7.40–7.43(2H, m), 7.65–7.72(2H, m), 8.64(1H, s), 14.04(1H, br). IR(KBr)cm⁻¹: 3438, 3061, 2688, 1747, 1637, 1567, 1463, 1244. Mass m/z: 364(M⁺).

3) Preparation of2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-cinnamyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one wasreacted to yield the title compound as slightly yellow needles (yield:20.1%).

Melting point: 139.9–140.9° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.34(3H, d,J=1.5 Hz), 3.00(1H, br), 4.73(2H, s), 5.01(2H, d, J=6.6 Hz), 6.44(1H,dt, J=15.9, 6.6 Hz), 6.72(2H, d, J=15.9 Hz), 7.08(1H, dd, J=8.9, 8.9Hz), 7.24(1H, t, J=7.3 Hz), 7.30(2H, dd, J=7.3, 7.3 Hz), 7.39(2H, d,J=7.3 Hz), 7.58–7.62(1H, m), 7.64(1H, d, J=7.3 Hz), 7.67(1H, s). IR(KBr)cm⁻¹: 3393, 1655, 1648, 1602, 1505, 1451, 1238, 1077. Mass m/z: 350(M⁺).

4) Preparation of2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless needles (yield:91.9%).

Melting point: 78.4–80.5° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.35(3H, d, J=2.0Hz), 3.17(3H, s), 5.10(2H, dd, J=1.2, 6.8 Hz), 5.28(2H, d, J=1.2 Hz),6.42(1H, dt, J=15.9, 6.8 Hz), 6.73(1H, d, J=15.9 Hz), 7.09(1H, dd,J=8.9, 8.9 Hz), 7.21–7.33(3H, m), 7.40(2H, d, J=8.8 Hz), 7.57–7.62(1H,m), 7.64(1H, d, J=8.8 Hz), 7.77(1H, t, J=1.3 Hz). IR(KBr) cm⁻¹: 1663,1612, 1508, 1355, 1241, 1167, 988, 958, 873. Mass m/z: 428(M⁺).

5) Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)-methyl-2-cinnamyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand tert-butyl 1-piperazinecarboxylate were reacted to yield the titlecompound as a yellow oil (yield: 86.7%).

¹H NMR(400 MHz, CDCl₃)δ: 1.47(9H, s), 2.35(3H, d, J=1.6 Hz), 2.52(4H, t,J=5.0 Hz), 3.51(4H, t, J=4.9 Hz), 3.59(2H, d, J=1.4 Hz), 5.00(2H, dd,J=1.0, 6.6 Hz), 6.45(1H, dt, J=15.8, 6.6 Hz), 6.72(1H, d, J=15.8 Hz),7.08(1H, dd, J=8.9, 8.9 Hz), 7.22(1H, t, J=7.2 Hz), 7.29(2H, dd, J=7.0,7.0 Hz), 7.38(2H, d, J=7.7 Hz), 7.56–7.61(1H, m), 7.65(1H, dd, J=1.8,7.2 Hz), 7.77(1H, s).

Example 133 Preparation of2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 2,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-cinnamyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 96.0%).

Melting point: 171.1–187.1° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:2.31(3H, d, J=2.0 Hz), 3.21(4H, t, J=4.9 Hz), 3.34(4H, t, J=5.1 Hz),3.99(2H, s), 4.95(2H, dd, J=1.3, 6.4 Hz), 6.45(1H, dt, J=16.1, 6.3 Hz),6.68(1H, d, J=16.1 Hz), 7.20–7.26(2H, m), 7.29–7.34(2H, m),7.41–7.45(2H, m), 7.73–7.79(1H, m), 7.83(1H, dd, J=1.7, 7.3 Hz),8.26(1H, s). IR(KBr) cm⁻¹: 1656, 1605, 1505, 1239, 962. Mass m/z:418(M⁺)

Example 134 Preparation of2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as ayellow oil (yield: 80.1%).

¹H NMR(400 MHz, CDCl₃)δ: 2.32(3H, s), 2.35(3H, d, J=1.8 Hz), 2.51(4H,br), 2.62(4H, br), 3.59(2H, d, J=1.4 Hz), 4.99(2H, dd, J=1.1, 6.6 Hz),6.45(1H, dt, J=15.8, 6.0 Hz), 6.72(1H, d, J=15.8 Hz), 7.08(1H, dd,J=8.9, 8.9 Hz), 7.22(1H, tt, J=1.6, 7.2 Hz), 7.29(2H, dd, J=7.2, 7.2Hz), 7.39(2H, dd, J=1.4, 7.2 Hz), 7.56–7.61(1H, m), 7.65(1H, dd, J=1.8,7.2 Hz), 7.75(1H, t, J=1.4 Hz).

Example 135 Preparation of2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 66.3%).

Melting point: 236.1–237.1° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 2.32(3H, d,J=2.2 Hz), 2.76(3H, s), 3.08(4H, br), 3.32(4H, br), 3.83(2H, s),4.94(2H, dd, J=1.2, 6.4 Hz), 6.45(1H, dt, J=16.1, 6.3 Hz), 6.67(1H, d,J=15.8 Hz), 7.19–7.26(2H, m), 7.29–7.34(2H,m), 7.41–7.44(2H,m),7.71–7.76(1H,m), 7.81(1H, dd, J=2.2, 7.6 Hz), 8.07(1H, s). IR(KBr) cm⁻¹:1652, 1607, 1505, 1239, 1129. Mass m/z: 432(M⁺)

Example 136 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cinnamyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as a yellowoil (yield: 83.7%).

¹H NMR(400 MHz, CDCl₃)δ: 2.32(3H, s), 2.69(4H, t, J=4.9 Hz), 3.65(4H, d,J=4.9 Hz), 3.69(2H, s), 4.98(2H, d, J=6.6 Hz), 6.41(1H, dt, J=15.8, 6.5Hz), 6.68(1H, d, J=15.8 Hz), 7.05(1H, dd, J=8.9, 8.9 Hz), 7.21(1H, t,J=7.2 Hz), 7.28(2H, dd, J=7.2, 7.2 Hz), 7.37(2H, d, J=7.6 Hz),7.58–7.63(1H, m), 7.66(1H, dd, J=1.8, 7.2 Hz), 7.81(1H, s).

Example 137 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cinnamyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cinnamyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 63.2%).

Melting point: 112.5–113.2° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 2.32(3H, d,J=1.9 Hz), 3.35(4H, t, J=5.1 Hz), 3.84(4H, t, J=5.1 Hz), 4.46(2H, s),4.98(2H, dd, J=1.5, 6.1 Hz), 6.45(1H, dt, J=15.8, 6.1 Hz), 6.69(1H, d,J=16.0 Hz), 7.21–7.27(2H, m), 7.29–7.34(2H, m), 7.41–7.44(2H, m),7.75–7.80(1H, m), 7.85(1H, dd, J=2.0, 7.3 Hz), 8.47(1H, s). IR(KBr)cm⁻¹: 1652, 1604, 1505, 1241, 971. Mass m/z: 419(M⁺—H₂O)

Example 138 Preparation of2-cinnamyl-4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 7,2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand dimethylamine were reacted to yield the title compound as a yellowoil (yield: 90.9%).

¹H NMR(400 MHz, CDCl₃)δ: 2.34(3H, d, J=2.0 Hz), 2.36(6H, s), 3.51(2H, d,J=1.4 Hz), 5.00(2H, dd, J=1.3, 6.8 Hz), 6.46(1H, dt, J=15.8, 6.6 Hz),6.72(1H, d, J=15.8 Hz), 7.07(1H, dd, J=8.9, 8.9 Hz), 7.22(1H, tt, J=1.4,7.2 Hz), 7.29(2H, dd, J=7.2, 7.2 Hz), 7.39(2H, dd, J=1.6, 7.0 Hz),7.60–7.65(1H, m), 7.67(1H, dd, J=2.2, 7.2 Hz), 7.76(1H, s).

Example 139 Preparation of2-cinnamyl-4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,2-cinnamyl-4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 81.1%).

Melting point: 183.6–184.5° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 2.32(3H, d,J=2.0 Hz), 2.83(6H, s), 4.29(2H, s), 4.98(2H, dd, J=1.3, 6.4 Hz),6.46(1H, dt, J=16.1, 6.3 Hz), 6.69(1H, d,J=16.1 Hz), 7.22–7.27(2H,m),7.29–7.35(2H,m), 7.41–7.44(2H, m), 7.76–7.81(1H, m), 7.86(1H, dd, J=2.2,7.3 Hz), 8.50(1H, s). IR(KBr) cm⁻¹: 1652, 1607, 1505, 1240, 965. Massm/z: 377(M⁺)

Example 140 Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one 1)Preparation of2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(3-fluoro-4-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and4-chlorocinnamyl chloride were reacted to yield the title compound asyellow needles (yield: 71.7%).

Melting point: 137.8–138.8° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.35(3H, d,J=1.7 Hz), 3.99(3H, s), 5.03(2H, d, J=6.6 Hz), 6.43(1H, dt, J=15.6, 6.6Hz), 6.70(1H, d, J=15.6 Hz), 7.10(1H, d, J=8.8 Hz), 7.27(2H, d, J=8.8Hz), 7.31(2H, d, J=8.8 Hz), 7.58–7.63(1H, m), 7.64(1H, dd, J=2.1, 7.0Hz), 8.24(1H, s). IR(KBr) cm⁻¹: 1724, 1709, 1667, 1506, 1291, 1236,1126, 831. Mass m/z: 412(M⁺), 414(M⁺).

2) Preparation of4-carboxy-2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(7),2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound as ayellow crystalline powder (yield: 86.2%).

Melting point: 186.0–186.6° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.36(3H, d,J=2.0 Hz), 5.11(2H, dd, J=1.2, 6.8 Hz), 6.39(1H, dt, J=15.9, 6.8 Hz),6.75(1H, d, J=15.6 Hz), 7.13(1H, dd, J=8.8, 8.8 Hz), 7.29(2H, d, J=8.5Hz), 7.33(2H, d, J=8.5 Hz), 7.65–7.71(2H, m), 8.64(1H, s), 13.98(1H,br). IR(KBr) cm⁻¹: 3471, 1738, 1631, 1566, 1490, 1467, 1403, 1242, 812,802. Mass m/z: 398(M⁺), 400(M⁺).

3) Preparation of2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow needles(yield: 17.2%).

Melting point: 131.8–133.1° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.34(3H, d,J=2.0 Hz), 4.73 (2H, d, J=1.2 Hz), 4.99(2H, dd, J=1.0, 6.6 Hz), 6.40(1H,dt, J=15.9, 6.6 Hz), 6.75(1H, d, J=15.9 Hz), 7.08(1H, dd, J=8.9, 8.9Hz), 7.26(2H, d, J=8.8 Hz), 7.31(2H, d, J=8.8. Hz), 7.57–7.62(1H, m),7.64(1H, dd, J=2.2, 7.3 Hz), 7.69(1H, t, J=1.2 Hz). IR(KBr) cm⁻¹: 3359,1653, 1598, 1506, 1492, 1240, 1091, 1076. Mass m/z: 384(M⁺), 386 (M⁺).

4) Preparation of2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless needles (yield:94.9%).

Melting point: 117.8–119.5° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.35(3H, d,J=2.0 Hz), 3.17(3H, s), 4.99(2H, dd, J=1.2, 6.6 Hz), 5.28(2H, d, J=1.2Hz), 6.38(1H, dt, J=15.9, 6.6 Hz), 6.75(1H, d, J=15.9 Hz), 7.10(1H, dd,J=8.8, 8.8 Hz), 7.27(2H, d, J=8.5 Hz), 7.32(2H, d, J=8.5. Hz),7.57–7.65(2H, m), 7.78(1H, t, J=1.3 Hz). IR(KBr) cm⁻¹: 1663, 1619, 1506,1492, 1346, 1240, 1172, 960, 830. Mass m/z: 462(M⁺), 464(M⁺).

5) Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)-methyl-2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand tert-butyl 1-piperazinecarboxylate were reacted to yield the titlecompound as a yellow oil (yield: 87.9%).

¹H NMR(400 MHz, CDCl₃)δ: 1.47(9H, s), 2.35(3H, d, J=1.6 Hz), 2.52(4H, t,J=4.9 Hz), 3.50(4H, t, J=5.0 Hz), 3.59(2H, d, J=1.2 Hz), 4.99(2H, dd,J=1.0, 6.6 Hz), 6.42(1H, dt, J=15.8, 6.6 Hz), 6.67(1H, d, J=16.0 Hz),7.09(1H, dd, J=8.9, 8.9 Hz), 7.25(2H, d, J=8.8 Hz), 7.31(2H, d, J=8.6Hz), 7.55–7.61(1H, m), 7.64(1H, dd, J=2.0, 7.2 Hz), 7.77(1H, s).

Example 141 Preparation of2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 2,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a pale brown crystallinepowder (yield: 84.7%).

Melting point: 186.7–197.0° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:2.31(3H, d, J=2.0 Hz), 3.15(4H, br), 3.31(4H, t, J=5.2 Hz), 3.94(2H, s),4.95(2H, dd, J=1.3, 6.3 Hz), 6.47(1H, dt, J=15.9, 6.1 Hz), 6.66(1H, d,J=15.9 Hz), 7.22(1H, dd, J=9.0, 9.0 Hz), 7.34(2H, d, J=8.6 Hz), 7.45(2H,d, J=8.6 Hz), 7.73–7.78(1H, m), 7.82(1H, dd, J=1.9, 7.6 Hz), 8.21(1H,s). IR(KBr) cm⁻¹: 1656, 1606, 1240, 1090, 964. Mass m/z: 452(M⁺),454(M⁺).

Example 142 Preparation of2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as ayellow oil (yield: 71.8%).

¹H NMR(400 MHz, CDCl₃)δ: 2.32(3H, s), 2.35(3H, s), 2.51(4H, br),2.62(4H, br), 3.59(2H, s), 4.99(2H, d, J=6.6 Hz), 6.42(1H, dt, J=15.8,6.4 Hz), 6.66(1H, d, J=15.9 Hz), 7.09(1H, dd, J=8.9, 8.9 Hz), 7.24(2H,d, J=8.6 Hz), 7.30(2H, d, J=8.6 Hz), 7.56–7.62(1H, m), 7.65(1H, dd,J=1.8, 7.2 Hz), 7.76(1H, s).

Example 143 Preparation of2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 80.4%).

Melting point: 229.7–243.3° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:2.31(3H, d, J=1.8 Hz), 2.76(3H, s), 3.09(4H, br), 3.33(4H, br), 3.83(2H,s), 4.94(2H, dd, J=1.2, 6.0 Hz), 6.42(1H, dt, J=16.0, 6.2 Hz), 6.65(1H,d, J=16.0 Hz), 7.22(1H, dd, J=9.1, 9.1 Hz), 7.34(2H, d, J=8.6 Hz),7.45(2H, d, J=8.6 Hz), 7.71–7.76(1H, m), 7.80(1H, dd, J=2.2, 7.0 Hz),8.08(1H, s). IR(KBr) cm⁻¹: 1652, 1608, 1492, 1239, 1130. Mass m/z:466(M⁺), 468(M⁺).

Example 144 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as a yellowoil (yield: 76.6%).

¹H NMR(400 MHz, CDCl₃)δ: 2.33(3H, s), 2.70(4H, t, J=4.5 Hz), 3.66(4H, t,J=4.9 Hz), 3.70(2H, s), 4.98(2H, d, J=6.6 Hz), 6.36(1H, dt, J=15.8, 6.5Hz), 6.63(1H, d, J=15.8 Hz), 7.06(1H, dd, J=8.6, 8.6 Hz), 7.24(2H, d,J=8.6 Hz), 7.30(2H, d, J=8.2 Hz), 7.58–7.63(1H, m), 7.65(1H, dd, J=1.8,7.2 Hz), 7.78(1H, s).

Example 145 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 76.1%).

Melting point: 151.9–153.4° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 2.32(3H, d,J=1.7 Hz), 3.35(4H, t, J=5.1 Hz), 3.83(4H, t, J=5.4 Hz), 4.46(2H, s),4.97(2H, dd, J=1.2, 6.1 Hz), 6.48(1H, dt, J=15.9, 6.2 Hz), 6.67(1H, d,J=15.9 Hz), 7.24(1H, dd, J=9.1, 9.1 Hz), 7.35(2H, d, J=8.8 Hz), 7.45(2H,d, J=8.6 Hz), 7.75–7.80(1H, m), 7.85(1H, dd, J=1.7, 7.9 Hz), 8.48(1H,s). IR(KBr) cm⁻¹: 1652, 1604, 1492, 1240, 1090, 968. Mass m/z: 440(M⁺),442(M⁺).

Example 146 Preparation of2-(4-chlorocinnamyl)-4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 7,2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 84.6%).

¹H NMR(400 MHz, CDCl₃)δ: 2.33(3H, d, J=1.6 Hz), 2.36(6H, s), 3.52(2H, d,J=1.2 Hz), 4.99(2H, dd, J=1.0, 6.6 Hz), 6.43(1H, dt, J=15.8, 6.6 Hz),6.66(1H, d, J=15.8 Hz), 7.07(1H, dd, J=8.9, 8.9 Hz), 7.24(2H, d, J=8.6Hz), 7.30(2H, d, J=8.6 Hz), 7.60–7.68(2H, m), 7.77(1H, s).

Example 147 Preparation of2-(4-chlorocinnamyl)-4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,2-(4-chlorocinnamyl)-4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 34.4%).

Melting point: 201.3–201.9° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 2.32(3H, d,J=1.7 Hz), 2.83(6H, s), 4.28(2H, s), 4.98(2H, dd, J=1.3, 6.1 Hz),6.48(1H, dt, J=16.1, 6.1 Hz), 6.67(1H, d, J=16.1 Hz), 7.24(1H, dd,J=9.3, 9.3 Hz), 7.35(2H, d, J=8.6 Hz), 7.45(2H, d, J=8.6 Hz),7.75–7.80(1H, m), 7.85(1H, dd, J=2.3, 7.6 Hz), 8.47(1H, s). IR(KBr)cm⁻¹: 1652, 1608, 1491, 1239, 968. Mass m/z: 411(M⁺), 413(M⁺).

Example 148 Preparation of2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one 1)Preparation of4-carboxy-2-cyclopropylmethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of Example 1(7),2-cyclopropylmethyl-4-methoxycarbonyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow crystalline powder(yield: 98.2%).

¹H NMR(400 MHz, CDCl₃)δ: 0.50–0.66(4H, m), 1.40–1.53(1H, m), 2.54(3H,s), 4.24(2H, d, J=7.4 Hz), 7.34 (2H, d, J=8.6 Hz), 7.78 (2H, d, J=8.6Hz), 8.66(1H, s), 14.22(1H, s). IR(KBr) cm⁻¹: 3430, 1752, 1631, 1472,1452, 1403, 1093, 825. Mass m/z: 316(M⁺)

2) Preparation of2-cyclopropylmethyl-4-hydroxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-cyclopropylmethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow crystallinepowder (yield: 22.6%).

¹H NMR(400 MHz, CDCl₃)δ: 0.45–0.60(4H, m), 1.37–1.46(1H, m), 2.53(3H,s), 3.09(1H, t, J=6.1 Hz), 4.11(2H, d, J=7.2 Hz), 4.72(2H, d, J=6.0 Hz),7.32(2H, d, J=8.6 Hz), 7.67(1H, s), 7.74(2H, d, J=8.6 Hz). IR(KBr) cm⁻¹:3393, 1657, 1602, 1514, 1095, 822. Mass m/z: 302(M⁺).

3) Preparation of2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-cyclopropylmethyl-4-hydroxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow fine-needles(yield: 78.6%).

¹H NMR(400 MHz, CDCl₃)δ: 0.45–1.61(4H, m), 1.37–1.47(1H, m), 2.53(3H,s), 3.17(3H, s), 4.11(2H, d, J=7.2 Hz), 5.28(2H, s), 7.33(2H, d, J=8.4Hz), 7.74(2H, d, J=8.4 Hz), 7.79(1H, s). IR(KBr) cm⁻¹: 3446, 1652, 1607,1359, 1178, 1024, 829. Mass m/z: 380(M⁺).

4) Preparation of2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as ayellow oil (yield: 85.7%).

¹H NMR(400 MHz, CDCl₃)δ: 0.44–0.58(4H, m), 1.36–1.48(1H, m), 2.33(3H,s), 2.53(3H, s), 2.47–2.66(8H, m), 3.59(2H, s), 4.10(2H, d, J=7.3 Hz),7.33(2H, d, J=8.3 Hz), 7.75(2H, d, J=8.3 Hz), 7.78(1H, s).

Example 149 Preparation of2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 69.1%).

Melting point: 234.6–239.2° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.40–0.45(2H,m), 0.50–0.56(2H, m), 1.30–1.40(1H, m), 2.53(3H, s), 2.77(3H, s),2.97(4H, br), 3.28(4H, br), 3.72(2H, s), 4.05(2H, d, J=7.1 Hz), 7.39(2H,d, J=8.6 Hz), 7.82(2H, d, J=8.3 Hz), 7.96(1H, s). IR(KBr) cm⁻¹: 3438,1651, 1606, 1402, 1095. Mass m/z: 384(M⁺).

Example 150 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as a yellowoil (yield: 78.9%).

¹H NMR(400 MHz, CDCl₃)δ: 0.44–0.59(4H, m), 1.36–1.45(1H, m), 2.53(3H,s), 2.73(4H, br), 3.67(4H, t, J=4.9 Hz), 3.73(2H, s), 4.13(2H, d, J=7.3Hz), 7.32(2H, d, J=8.3 Hz), 7.70(1H, s), 7.74(2H, d, J=8.3 Hz).

Example 151 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a slightly yellow solid(yield: 75.1%).

Melting point: 169.2–171.7° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.42–0.46(2H,m), 0.52–0.57(2H, m), 1.30–1.40(1H, m), 2.53(3H, s), 3.31(4H, br),3.81(4H, t, J=5.3 Hz), 4.42(2H, s), 7.41(2H, d, J=8.8 Hz), 7.85(2H, d,J=9.0 Hz), 8.37(1H, s). IR(KBr) cm⁻¹: 3242, 1652, 1604, 1420, 1094,1059, 823. Mass m/z: 358 (M⁺—CH₂OH).

Example 152 Preparation of2-cyclopropylmethyl-4-dimethylaminomethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of Example 7,2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 98.6%).

¹H NMR(400 MHz, CDCl₃)δ: 0.44–0.58(4H, m), 1.36–1.48(1H, m), 2.35(6H,s), 3.51(2H, s), 4.51(2H, d, J=7.3 Hz), 7.31(2H, d, J=8.3 Hz), 7.77(2H,d, J=7.8 Hz), 7.78(1H, s).

Example 153 Preparation of2-cyclopropylmethyl-4-dimethylaminomethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,2-cyclopropylmethyl-4-dimethylaminomethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow crystallinepowder (yield: 75.5%).

Melting point: 230.2–232.3° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.42–0.46(2H,m), 0.52–0.58(2H, m), 1.31–1.40(1H, m), 2.53(3H, s), 2.82(6H, s),4.09(2H, d, J=7.1 Hz), 4.25(2H, s), 7.41(2H, d, J=8.6 Hz), 7.84(2H, d,J=8.5 Hz), 8.34(1H, s). IR(KBr) cm⁻¹: 3435, 1646, 1604, 1402, 1093, 829.Mass m/z: 329(M⁺).

Example 154 Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one 1)Preparation of4-carboxy-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

To a solution of4-methoxycarbonyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one (8.00 g,29.0 mmol) in N,N-dimethylformamide (80 mL) were added potassiumcarbonate (8.02 g, 58.0 mmol) and isobutyl bromide (4.76 g, 34.8 mmol),and the mixture was stirred at 80° C. for 2 hours. The temperature ofthe reaction mixture was allowed to drop back to room temperature, and asaturated aqueous solution of sodium hydrogencarbonate was added. Themixture was then extracted with ethyl acetate. The extract was washedwith brine, and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. Following the procedure of Example1(7), the residue was reacted to yield the title compound as a yellowsolid [yield: 65.1% (2 steps)].

¹H NMR(400 MHz, CDCl₃)δ: 1.01(6H, d, J=6.6 Hz), 2.33–2.46(1H, m),2.54(3H, s), 4.21(2H, d, J=7.4 Hz), 7.34(2H, d, J=8.4 Hz), 7.80(2H, d,J=8.4 Hz), 8.68(1H, s), 12.72(1H, s). Mass m/z: 318(M⁺).

2) Preparation of4-hydroxymethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one wasreacted to yield the title compound as a yellow oil (yield: 35.3%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.6 Hz), 2.27–2.39(1H, m),2.53(3H, s), 4.08(2H, d, J=7.4 Hz), 4.71(2H, d, J=5.9 Hz), 7.26(2H, d,J=8.4 Hz), 7.66(1H, s), 7.73(2H, d, J=8.6 Hz).

3) Preparation of2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of Example 1(9),4-hydroxymethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow crystallinepowder (yield: 73.2%).

¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d, J=6.6 Hz), 2.28–2.40(1H, m),2.53(3H, s), 3.17(3H, s), 4.08(2H, d, J=7.4 Hz), 5.27(2H, d, J=1.2 Hz),7.32(2H, d, J=8.4 Hz), 7.73(2H, d, J=8.4 Hz), 7.75(1H, d, J=1.4 Hz).Mass m/z: 382(M⁺).

4) Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-isobutyl-4-methanesulfonyloxymethyl-6-[47(methylthio)phenyl]-2H-pyridazin-3-one and tert-butyl1-piperazinecarboxylate were reacted to yield the title compound as ayellow oil (yield: 88.0%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.6 Hz), 1.47(9H, s),2.28–2.40(1H, m), 2.50–2.55(4H, m), 2.53(3H, s), 3.50(4H, t, J=4.8 Hz),3.58(2H, s), 4.07(2H, d, J=7.4 Hz), 7.32(2H, d, J=8.4 Hz), 7.73(2H, d,J=8.6 Hz), 7.78(1H, s).

Example 155 Preparation of2-isobutyl-6-[4-(methylthio)phenyl]-4-(1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 2,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow crystalline powder(yield: 70.5%).

Melting point: 248.5–253.7° C. (dec.). ¹H NMR(400 MHz, DMSO-d₆)δ:0.95(6H, d, J=6.6 Hz), 2.21–2.33(1H, m), 2.52(3H, s), 3.10(4H, t, J=4.8Hz), 3.30(4H, t, J=5.2 Hz), 3.90(2H, s), 4.01(2H, d, J=7.3 Hz), 7.39(2H,d, J=8.3 Hz), 7.83(2H, d, J=8.3 Hz), 8.15(1H, s). IR(KBr) cm⁻¹: 2961,2442, 1640, 1596, 1511, 1433, 1406, 1089, 912. Mass m/z: 372(M⁺).

Example 156 Preparation of2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as ayellow oil (yield: 68.3%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.6 Hz), 2.29–2.39(1H, m),2.32(3H, s), 2.51(4H, br), 2.53(3H, s), 2.62(4H, br), 3.58(2H, d, J=1.4Hz), 4.07(2H, d, J=7.4 Hz), 7.33(2H, d, J=8.6 Hz), 7.74(2H, d, J=6.8Hz), 7.76(1H, s).

Example 157 Preparation of2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 86.4%).

Melting point: 242.6–243.7° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.94(6H, d,J=6.6 Hz), 2.21–2.33(1H, m), 2.52(3H, s), 2.76(3H, s), 3.09(4H, br),3.33(4H, br), 3.83(2H, s), 4.01(2H, d, J=7.1 Hz), 7.39(2H, d, J=8.6 Hz),7.82(2H, d, J=8.5 Hz), 8.07(1H, s). IR(KBr) cm⁻¹: 3432, 2957, 2437,1652, 1607, 1090, 953. Mass m/z: 386(M⁺).

Example 158 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as a yellowoil (yield: 71.2%).

¹H NMR(400 MHz, CDCl₃)δ: 0.96(6H, d, J=6.6 Hz), 2.27–2.39(1H, m),2.51(3H, s), 2.71(4H, t, J=5.1 Hz), 3.66(4H, t, J=5.1 Hz), 3.70(2H, s),4.08(2H, d, J=7.2 Hz), 7.30(2H, d, J=8.6 Hz), 7.71–7.76(3H, m).

Example 159 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneoxalate

To a solution of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one(69.7 mg, 0.18 mmol) in methanol (1 mL) was added at room temperatureoxalic acid dihydrate (22.4 mg, 0.18 mmol). The solvent was distilledoff under reduced pressure. The residue was recrystallized fromchloroform-diethyl ether to obtain the title compound as a white solid(59.5 mg, 69.4%).

Melting point: 116.4–118.1° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.94(6H, d,J=6.6 Hz), 2.20–2.33(1H, m), 2.52(3H, s), 2.91(4H, t, J=5.8 Hz),3.61(4H, t, J=5.6 Hz), 3.94(2H, s), 4.01(2H, d, J=7.3 Hz), 7.39 (2H, d,J=8.6 Hz), 7.81 (2H, d, J=8.6 Hz), 8.14(1H, s). IR(KBr) cm⁻¹: 3344,2927, 1659, 1611, 1402, 1049, 721. Mass m/z: 360(M⁺—CH₂OH).

Example 160 Preparation of4-dimethylaminomethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of Example 7,2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 73.9%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.6 Hz), 2.29–2.41(1H, m),2.36(6H, s), 2.52(3H, s), 3.52(2H, d, J=1.2 Hz), 4.07(2H, d, J=7.4 Hz),7.31(2H, d, J=8.6 Hz), 7.77(2H, d, J=8.4 Hz), 7.79(1H, s).

Example 161 Preparation of4-dimethylaminomethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-dimethylaminomethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 82.3%).

Melting point: 216.8–218.4° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.96(6H, d,J=6.8 Hz), 2.23–2.36(1H, m), 2.53(3H, s), 2.82(6H, s), 4.05(2H, d, J=7.1Hz), 4.27(2H, s), 7.41(2H, d, J=8.3 Hz), 7.84(2H, d, J=8.3 Hz), 8.42(1H,s). IR(KBr) cm⁻¹: 3485, 1740, 1684, 1253, 856, 577. Mass m/z: 331(M⁺).

Example 162 Preparation of2-isobutyl-6-[4-(methylthio)phenyl]-4-propargylaminomethyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneand propargylamine were reacted to yield the title compound as a yellowoil (yield: 52.2%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.6 Hz), 2.26(1H, t, J=2.3 Hz),2.29–2.40(1H, m), 2.52(3H, s), 3.51(2H, d, J=2.4 Hz), 3.90(2H, s),4.07(2H, d, J=7.4 Hz), 7.31(2H, d, J=8.4 Hz), 7.70(1H, s), 7.73(2H, d,J=8.4 Hz).

Example 163 Preparation of2-isobutyl-6-[4-(methylthio)phenyl]-4-propargylaminomethyl-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,2-isobutyl-6-[4-(methylthio)phenyl]-4-propargylaminomethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a white solid (yield: 73.6%).

Melting point: 197.5–198.4° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.96(6H, d,J=6.6 Hz), 2.23–2.36(1H, m), 2.53(3H, s), 3.48(1H, t, J=2.4 Hz),3.95(2H, d, J=2.4 Hz), 4.03(2H, d, J=7.1 Hz), 4.17(2H, s), 7.41(2H, d,J=8.3 Hz), 7.82(2H, d, J=8.6 Hz), 8.28(1H, s). IR(KBr) cm⁻¹: 3447, 3207,2958, 2122, 1651, 1607, 1441, 1093. Mass m/z: 341(M⁺).

Example 164 Preparation of2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one 1)Preparation of2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

To a solution of2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one(300 mg, 0.79 mmol) in methylene chloride (10 mL) was added dropwise at−20° C. a solution of 3-chloroperbenzoic acid (204 mg, 1.12 mmol) inmethylene chloride (2 mL), and at the same temperature, the mixture wasstirred for 30 minutes. A 10% aqueous sodium hydrogensulfite was addedto the reaction mixture, and then, the mixture was extracted withchloroform. The extract was successively washed with a saturated aqueoussodium hydrogencarbonate and brine, and was then dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure.The residue was recrystallized from chloroform-hexane to yield the titlecompound as a colorless crystalline powder (139 mg, 44.5%).

¹H NMR(400 MHz, CDCl₃)δ: 0.48–0.63(4H, m), 1.37–1.46(1H, m), 2.77(3H,s), 3.18(3H, s), 4.14(2H, d, J=7.3 Hz), 5.30(2H, d, J=1.4 Hz), 7.76(2H,d, J=8.6 Hz), 7.84(1H, t, J=1.4 Hz), 7.98(2H, d, J=8.8 Hz). Mass m/z:396(M⁺).

2) Preparation of2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methyl-sulfinyl)phenyl]-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as ayellow oil (yield: 60.6%).

¹H NMR(400 MHz, CDCl₃)δ: 0.46–0.60(4H, m), 1.37–1.49(1H, m), 2.34(3H,s), 2.54(4H, br), 2.64(4H, br), 2.78(3H, s), 3.61(2H, s), 4.13(2H, d,J=7.2 Hz), 7.75(2H, d, J=8.2 Hz), 7.84(1H, s), 7.99(2H, d, J=8.2 Hz).

Example 165 Preparation of2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 64.3%).

Melting point: 80° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ: 0.41–0.57(4H,m), 1.30–1.41(1H, m), 2.76(3H, s), 2.77(3H, s), 3.01(4H, br), 3.31(4H,br), 3.77(2H, s), 4.08(2H, d, J=6.8 Hz), 7.80(2H, d, J=8.3 Hz),8.05–8.09(3H, m). IR(KBr) cm⁻¹: 3430, 3005, 1652, 1607, 1458, 1401,1010, 838. Mass m/z: 400(M⁺).

Example 166 Preparation of2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one 1)Preparation of2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

Following the procedure of Example 166(1),2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 54.3%).

¹H NMR(400 MHz, CDCl₃)δ: 1.00(6H, d, J=6.8 Hz), 2.29–2.41(1H, m),2.77(3H, s), 3.18(3H, s), 4.11(2H, d, J=7.3 Hz), 5.29(2H, d, J=1.5 Hz),7.76(2H, d, J=8.8 Hz), 7.83(1H, t, J=1.2 Hz), 7.98(2H, d, J=8.6 Hz).Mass m/z: 398(M⁺).

2) Preparation of2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as ayellow oil (yield: 61.8%).

¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d, J=6.6 Hz), 2.30–2.41(1H, m),2.34(3H, s), 2.54(4H, br), 2.64(4H, br), 2.77(3H, s), 3.60(2H, s),4.10(2H, d, J=7.4 Hz), 7.75(2H, d, J=8.2 Hz), 7.82(1H, s), 7.99(2H, d,J=8.2 Hz).

Example 167 Preparation of2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 76.1%).

Melting point: 224.5–229.1° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:0.96(6H, d, J=6.6 Hz), 2.22–2.35(1H, m), 2.76(3H, s), 2.77(3H, s),3.14(4H, br), 3.35(4H, br), 3.87(2H, s), 4.04(2H, d, J=7.1 Hz), 7.80(2H,d, J=8.3 Hz), 8.07(2H, d, J=8.3 Hz), 8.18(1H, s). IR(KBr) cm⁻¹: 3426,2960, 1656, 1608, 1459, 1400, 1044, 1011. Mass m/z: 402(M⁺).

Example 168 Preparation of4-dimethylaminomethyl-2-isobutyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

Following the procedure of Example 7,2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 46.2%).

¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d, J=6.8 Hz), 2.30–2.43(1H, m),2.38(6H, s), 2.76(3H, s), 3.54(2H, s), 4.10(2H, d, J=7.4 Hz), 7.74(2H,d, J=8.2 Hz), 7.87(1H, s), 8.02(2H, d, J=8.2 Hz).

Example 169 Preparation of4-dimethylaminomethyl-2-isobutyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-dimethylaminomethyl-2-isobutyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 77.4%).

Melting point: 204.2–206.0° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.97(6H, d,J=6.6 Hz), 2.24–2.36(1H, m), 2.78(3H, s), 2.83(6H, s), 4.07(2H, d, J=7.1Hz), 4.28(2H, s), 7.82(2H, d, J=8.3 Hz), 8.09(2H, d, J=8.3 Hz), 8.49(1H,s). IR(KBr) cm⁻¹: 3438, 2961, 1652, 1607, 1467, 1400, 1047. Mass m/z:347(M⁺).

Example 170 Preparation of2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one 1)Preparation of2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

To a solution of2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one(226 mg, 0.59 mmol) in methylene chloride (10 mL) was added dropwise at−20° C. a solution of 3-chloroperbenzoic acid (410 mg, 2.38 mmol) inmethylene chloride (2 mL), and at the same temperature, the mixture wasstirred for 30 minutes. A 10% aqueous sodium hydrogensulfite was addedto the reaction mixture, and then, the mixture was extracted withchloroform. The extract was successively washed with a saturated aqueoussodium hydrogencarbonate and brine, and was then dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure.The residue was recrystallized from chloroform-hexane to yield the titlecompound as a colorless crystalline powder (209 mg, 85.3%).

¹H NMR(400 MHz, CDCl₃)δ: 0.46–0.63(4H, m), 1.37–1.46(1H, m), 3.10(3H,s), 3.18(3H, s), 4.20(2H, d, J=7.3 Hz), 5.31(2H, d, J=1.2 Hz), 7.86(1H,t, J=1.2 Hz), 8.02(2H, d, J=8.8 Hz), 8.06(2H, d, J=9.0 Hz). Mass m/z:412(M⁺).

2) Preparation of2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methyl-sulfonyl)phenyl]-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as ayellow oil (yield: 80.9%).

¹H NMR(400 MHz, CDCl₃)δ: 0.46–0.61(4H, m), 1.38–1.48(1H, m), 2.34(3H,s), 2.54(4H, br), 2.64 (4H, br), 3.10 (3H, s), 3.61 (2H, d, J=1.2 Hz),4.13 (2H, d, J=7.1 Hz), 7.85(1H, t, J=11.2 Hz), 8.03(2H, d, J=9.0 Hz),8.05(2H, d, J=9.0 Hz).

Example 171 Preparation of2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 76.8%).

Melting point: 209.0–211.4° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.41–0.46(2H,m), 0.52–0.57(2H, m), 1.31–1.41(1H, m), 2.77(3H, s), 3.04(4H, br),3.21(3H, s), 3.31(4H, br), 3.80(2H, s), 4.09(2H, d, J=7.1 Hz), 8.04(2H,d, J=8.3 Hz), 8.12(1H, s), 8.14(2H, d, J=8.3 Hz). IR(KBr) cm⁻¹: 3434,3012, 1652, 1596, 1458, 1402, 1302, 1150. Mass m/z: 416(M⁺).

Example 172 Preparation of2-cyclopropylmethyl-4-dimethylaminomethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-oneand dimethylamine were reacted to yield the title compound as a yellowoil (yield: 65.6%).

¹H NMR(400 MHz, CDCl₃)δ: 0.45–0.62(4H, m), 1.39–1.49(1H, m), 2.38(6H,s), 3.09(3H, s), 3.55(2H, s), 4.14(2H, d, J=7.2 Hz), 7.89(1H, s),8.02(2H, d, J=8.4 Hz), 8.06(2H, d, J=8.6 Hz).

Example 173 Preparation of2-cyclopropylmethyl-4-dimethylaminomethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,2-cyclopropylmethyl-4-dimethylaminomethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 63.4%).

Melting point: 239.5–240.7° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.43–0.59(4H,m), 1.33–1.43(1H, m), 2.83(6H, s), 3.23(3H, s), 4.13(2H, d, J=7.1 Hz),4.29(2H, s), 8.06(2H, d, J=7.8 Hz), 8.17(2H, d, J=8.3 Hz), 8.57(1H, s).IR(KBr) cm⁻¹: 3447, 2674, 1646, 1608, 1596, 1306, 1150, 777. Mass m/z:361(M⁺).

Example 174 Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-isobutyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one 1)Preparation of2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

Following the procedure of Example 170(1),2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 97.8%).

¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d, J=6.6 Hz), 2.29–2.41(1H, m),3.10(3H, s), 3.18(3H, s), 4.12(2H, d, J=7.3 Hz), 5.29(2H, d, J=1.2 Hz),7.85(1H, t, J=1.4 Hz), 8.02(2H, d, J=8.8 Hz), 8.05(2H, d, J=8.8 Hz).Mass m/z: 414(M⁺).

2) Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-isobutyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-oneand tert-butyl 1-piperazinecarboxylate were reacted to yield the titlecompound as a yellow oil (yield: 75.9%).

¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d, J=6.6 Hz), 1.47(9H, s),2.29–2.41(1H, m), 2.54(4H, br), 3.09(3H, s), 3.51(4H, br), 3.60(2H, s),4.11(2H, d, J=7.2 Hz), 7.86(1H, s), 8.02(2H, d, J=8.8 Hz), 8.05(2H, d,J=8.8 Hz).

Example 175 Preparation of2-isobutyl-6-[4-(methylsulfonyl)phenyl]-4-(1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 2,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-isobutyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 88.2%).

Melting point: 222.4–224.2° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.96(6H, d,J=6.8 Hz), 2.22–2.35(1H, m), 3.06(4H, br), 3.21(3H, s), 3.28(4H, t,J=5.2 Hz), 3.87(2H, s), 4.05(2H, d, J=7.1 Hz), 8.04(2H, d, J=8.6 Hz),8.14(2H, d, J=8.3 Hz), 8.22(1H, s). IR(KBr) cm⁻¹: 3421, 2957, 1656,1611, 1597, 1305, 1149, 961. Mass m/z: 404(M⁺).

Example 176 Preparation of2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as ayellow oil (yield: 88.5%).

¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d, J=6.8 Hz), 2.28–2.40(1H, m),2.37(3H, s), 2.53(4H, br), 2.63(4H, br), 3.10(3H, s), 3.60(2H, s),4.10(2H, d, J=7.3 Hz), 7.84(1H, s), 8.02(2H, d, J=9.0 Hz), 8.05(2H, d,J=8.8 Hz).

Example 177 Preparation of2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 62.0%).

Melting point: 224.5–228.0° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.95(6H, d,J=6.8 Hz), 2.23–2.35(1H, m), 2.76(3H, s), 3.08(4H, br), 3.21(3H, s),3.32(4H, br), 3.83(2H, s), 4.05(2H, d, J=7.1 Hz), 8.04(2H, d, J=8.3 Hz),8.13(2H, d, J=8.5 Hz), 8.15(1H, s). IR(KBr) cm⁻¹: 3447, 2958, 1652,1610, 1596, 1319, 1152, 955. Mass m/z: 418 (M⁺).

Example 178 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as a yellowoil (yield: 51.1%).

¹H NMR(400 MHz, CDCl₃)δ: 0.98(6H, d, J=6.6 Hz), 2.28–2.40(1H, m),2.73(4H, t, J=4.8 Hz), 3.08(3H, s), 3.68(4H, t, J=4.9 Hz), 3.73(2H, s),4.11(2H, d, J=7.4 Hz), 7.93(1H, s), 8.00(2H, d, J=8.6 Hz), 8.05(2H, d,J=8.8 Hz). Mass m/z: 392(M⁺—CH₂OH).

Example 179 Preparation of4-dimethylaminomethyl-2-isobutyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

Following the procedure of Example 7,2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 82.1%).

¹H NMR(400 MHz, CDCl₃)δ: 0.99(6H, d, J=6.6 Hz), 2.30–2.41(1H, m),2.37(6H, s), 3.09(3H, s), 3.52(2H, s), 4.11(2H, d, J=7.2 Hz), 7.86(1H,s), 8.02(2H, d, J=8.8 Hz), 8.05(2H, d, J=8.8 Hz).

Example 180 Preparation of4-dimethylaminomethyl-2-isobutyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-dimethylaminomethyl-2-isobutyl-6-[4-(methylsulfonyl)-phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 58.6%).

Melting point: 221.4–223.3° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.97(6H, d,J=6.6 Hz), 2.25–2.36(1H, m), 2.82(6H, s), 3.22(3H, s), 4.08(2H, d, J=7.3Hz), 4.28(2H, s), 8.06(2H, d, J=8.3 Hz), 8.15(2H, d, J=8.5 Hz), 8.55(1H,s). IR(KBr) cm⁻¹: 3447, 2963, 1653, 1609, 1597, 1307, 1152, 777. Massm/z: 363(M⁺).

Example 181 Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-pyrrolidinomethyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand pyrrolidine were reacted to yield the title compound as a yellow oil(yield: 75.9%).

¹H NMR(400 MHz, CDCl₃)δ: 0.44–0.61(4H, m), 1.42(1H, m), 1.85–2.00(4H,m), 2.70–3.00(4H, m), 3.83(2H, brs), 3.94 (3H, s), 4.10 (2H, d, J=7.3Hz), 7.03(1H, dd, J=8.5, 8.5 Hz), 7.60(1H, d, J=8.5 Hz), 7.65(1H, dd,J=8.5, 2.0 Hz), 8.00(1H, brs). IR(Neat) cm⁻¹: 1652, 1608, 1523, 1438,1286, 758. Mass m/z: 357(M⁺).

Example 182 Preparation of2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one 1)Preparation of2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one andcyclopentylmethyl bromide {J. Org. Chem., 36, 3103 (1971)} were reactedto yield the title compound as yellow needles (yield: 72.0%).

Melting point: 56–66° C. ¹H NMR(400 MHz, CDCl₃)δ: 1.30–1.45(2H, m),1.53–1.65(2H, m), 1.65–1.80(4H, m), 2.57(1H, m), 3.95(3H, s), 3.98(3H,s), 4.24(2H, d, J=7.8 Hz), 7.03(1H, dd, J=8.5, 8.5 Hz), 7.50(1H, d,J=8.8 Hz), 7.61(1H, d, J=10.2 Hz), 8.19(1H, s).

2) Preparation of4-carboxy-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(7),2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow powder (yield:71.1%).

Melting point: 159–161° C. ¹H NMR(400 MHz, CDCl₃)δ: 1.33–1.45(2H, m),1.58–1.65(2H, m), 1.68–1.82(4H, m), 2.57(1H, m), 3.97(3H, s), 4.32(2H,d, J=7.6 Hz), 7.06(1H, dd, J=8.5, 8.5 Hz), 7.56(1H, d, J=8.5 Hz),7.68(1H, dd, J=12.2, 2.0 Hz), 8.61(1H, s).

3) Preparation of2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow powder (yield:47.3%).

Melting point: 130–133° C. ¹H NMR(400 MHz, CDCl₃)δ: 1.30–1.42(2H, m),1.50–1.62(2H, m), 1.62–1.80(4H, m), 2.54(1H, m), 3.95(3H, s), 4.19(2H,d, J=7.6 Hz), 4.71(2H, s), 7.02(1H, dd, J=8.5, 8.5 Hz), 7.51(1H, d,J=8.5 Hz), 7.62(1H, dd, J=12.8, 1.5 Hz), 7.63(1H, s).

4) Preparation of2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow powder (yield:75.3%).

Melting point: 108–116° C. ¹H NMR(400 MHz, CDCl₃)δ: 1.25–1.32(2H, m),1.32–1.45(2H, m), 1.65–1.77(4H, m), 2.54(1H, m), 3.17(3H, s), 3.95(3H,s), 4.19(2H, d, J=7.6 Hz), 5.27(2H, s), 7.03(1H, dd, J=8.5, 8.5 Hz),7.50(1H, d, J=8.5 Hz), 7.62(1H, dd, J=12.2, 2.2 Hz), 7.74(1H, s).

5) Preparation of2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as ayellow oil (yield: 61.4%).

¹H NMR(400 MHz, CDCl₃)δ: 1.32–1.42(2H, m), 1.50–1.60(2H, m),1.65–1.80(4H, m), 2.38, 2.40(each s, 3H in total), 2.54(1H, m),2.60–2.75(8H, m), 3.59(2H, s), 3.95(3H, s), 4.18(2H, d, J=7.6 Hz),7.04(1H, dd, J=8.5, 8.5 Hz), 7.54(1H, d, J=8.5 Hz), 7.61(1H, dd, J=8.5,2.2 Hz), 7.72(1H, s). IR(Neat) cm⁻¹: 1652, 1608, 1523, 1439, 1286, 760.Mass m/z: 414(M⁺).

Example 183 Preparation of2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale brown crystallinepowder (yield: 59.6%).

Melting point: 234–236° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:1.28–1.40(2H, m), 1.48–1.56(2H, m), 1.60–1.73(4H, m), 2.46(1H, m),2.82(3H, s), 3.50–3.75(10H, m), 3.91(3H, s), 4.10(2H, d, J=7.6 Hz),7.31(1H, dd, J=8.8, 8.8 Hz), 7.68–7.76(2H, m), 8.25(1H, s). IR(KBr)cm⁻¹: 1652, 1606, 1523, 1439, 1292, 764.

Example 184 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as a yellowoil (yield: 54.9%).

¹H NMR(400 MHz, CDCl₃)δ: 1.30–1.45(2H, m), 1.50–1.62(2H, m),1.62–1.80(4H, m), 2.53(1H, m), 2.75–2.90(4H, m), 3.70–3.75(4H, m),3.80–3.85(2H, m), 3.94(3H, s), 4.20(2H, d, J=7.6 Hz), 7.02(1H, dd,J=8.5, 8.5 Hz), 7.56(1H, d, J=8.5 Hz), 7.63(1H, dd, J=8.5, 2.0 Hz), 7.65(1H, m). IR(Neat) cm⁻¹: 1648, 1598, 1523, 1439, 1267, 728. Mass m/z:383(M^(+–2)H₂O).

Example 185 Preparation of2-cyclopentylmethyl-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 7,2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand dimethylamine were reacted to yield the title compound as a yellowoil (yield: 63.7%).

¹H NMR(400 MHz, CDCl₃)δ: 1.30–1.45(2H, m), 1.50–1.63(2H, m),1.63–1.80(4H, m), 2.43(6H, s), 2.55(1H, m), 3.61(2H, s), 3.94(3H, s),4.19(2H, d, J=7.6 Hz), 7.20(1H, d, J=8.5, 8.5 Hz), 7.58(1H, d, J=8.5Hz), 7.65(1H, dd, J=8.5, 2.2 Hz), 7.91(1H, brs). IR(Neat) cm⁻¹: 1652,1608, 1523, 1438, 1288, 762. Mass m/z: 359(M⁺).

Example 186 Preparation of2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one 1)Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand tert-butyl 1-piperazinecarboxylate were reacted to yield the titlecompound as a yellow oil (yield: 78.8%).

¹H NMR(400 MHz, CDCl₃)δ: 1.35–1.43(2H, m), 1.47(9H, s), 1.55–1.60(2H,m), 1.65–1.75(4H, m), 2.45–2.60 (5H, m), 3.45–3.55(4H, m), 3.95(3H, s),4.18(2H, d, J=7.6 Hz), 7.03(1H, dd, J=8.5, 8.5 Hz), 7.52(1H, m),7.62(1H, d, J=12.4 Hz), 7.74(1H, m).

2) Preparation of2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 20,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 88.0%).

¹H NMR(400 MHz, CDCl₃)δ: 1.33–1.43(2H, m), 1.50–1.62(2H, m),1.62–1.80(4H, m), 2.55(1H, m), 2.57–2.63(4H, m), 3.00–3.02(4H, m),3.56(2H, brs), 3.95(3H,s), 4.18(2H, d, J=7.6 Hz), 7.04(1H, dd, J=8.5,8.5 Hz), 7.52(1H, d, J=8.5 Hz), 7.62(1H, dd, J=8.5, 2.2 Hz), 7.73(1H,s). IR(Neat) cm⁻¹: 1652, 1608, 1523, 1439, 1287, 761. Mass m/z: 400(M⁺).

Example 187 Preparation of4-aminomethyl-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 24(1),2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield a crude product. Without purification, the crudeproduct was reacted further in accordance with the procedure of Example24(2) to yield the title compound as a yellow oil (yield: 53.7%).

¹H NMR(400 MHz, CDCl₃)δ: 1.30–1.45(2H, m), 1.50–1.63(2H, m),1.63–1.80(4H, m), 2.54(1H, m), 3.91(2H, s), 3.93(3H, s), 4.17(2H, d,J=7.6 Hz), 7.01(1H, dd, J=8.5, 8.5 Hz), 7.52(1H, d, J=8.5 Hz), 7.62(1H,dd, J=8.5, 2.2 Hz), 7.71(1H, brs). IR(Neat) cm⁻¹: 3376, 1649, 1606,1523, 1439, 1285, 761. Mass m/z: 331(M⁺).

Example 188 Preparation of4-aminomethyl-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-aminomethyl-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a slightly-yellow crystallinepowder (yield: 59.0%).

Melting point: 193–196° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 1.29–1.40(2H, m),1.45–1.57(2H, m), 1.60–1.70(4H, m), 2.45(1H, m), 3.91(3H, s), 4.00(2H,s), 4.12(2H, d, J=7.6 Hz), 7.34(1H, dd, J=8.5, 8.5 Hz), 7.69–7.72(2H,m), 8.47(1H, brs). IR(KBr) cm⁻¹: 3436, 1656, 1617, 1521, 1438, 1295,763.

Example 189 Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one 1)Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and4-fluorobenzyl chloride were reacted to yield the title compound as aslightly-yellow crystalline powder (yield: 86.6%).

¹H NMR(400 MHz, CDCl₃)δ: 3.95(3H, s), 3.97(3H, s), 5.39(2H, s),7.00–7.06(3H, m), 7.48–7.63(4H, m), 8.19(1H, s).

2) Preparation of4-carboxy-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(7),2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow powder (yield:97.7%).

Melting point: 222–224° C. ¹H NMR(400 MHz, CDCl₃)δ: 3.97(3H, s),5.47(2H, s), 7.03–7.10(3H, m), 7.49–7.56(3H, m), 7.67(1H, dd, J=12.1,2.2 Hz), 8.60(1H, s).

3) Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow powder (yield:27.0%).

Melting point: 127–130° C. ¹H NMR(400 MHz, CDCl₃)δ: 3.95(3H, s),4.79(2H, d, J=1.5 Hz), 5.36(2H, s), 6.98–7.05(3H, m), 7.46–7.52(3H, m),7.61(1H, dd, J=12.2, 2.2 Hz), 7.65(1H, s).

4) Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow powder (yield:49.4%).

Melting point: 125–133° C. ¹H NMR(400 MHz, CDCl₃)δ: 3.15(3H, s),3.95(3H, s), 5.25(2H, d, J=1.2 Hz), 5.35(2H, s), 7.00–7.06(3H, m),7.45–7.55(3H, m), 7.61(1H, dd, J=12.4, 2.2 Hz), 7.74(1H, s).

5) Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand 1-methylpiprazine were reacted to yield the title compound as aslightly-brown crystalline powder (yield: 45.8%).

Melting point: 112–113° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.39(3H, s),2.60–2.90(8H, m), 3.60(2H, s), 3.95(3H, s), 5.34(2H, s), 6.99–7.06(3H,m), 7.47–7.51(3H, m), 7.59(1H, dd, J=12.4, 2.0 Hz), 7.71(1H, s). IR(KBr)cm⁻¹: 1651, 1608, 1518, 1439, 1289, 764. Mass m/z: 440(M⁺).

Example 190 Preparation of4-dimethylaminomethyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 7,2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand dimethylamine were reacted to yield the title compound as aslightly-yellow crystalline powder (yield: 60.8%).

Melting point: 127–129° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.41(6H, s),3.58(2H, s), 3.94(3H, s), 5.35(2H, s), 6.98–7.05(3H, m), 7.46–7.52(2H,m), 7.56(1H, d, J=8.8 Hz), 7.64(1H, dd, J=12.4, 2.2 Hz), 7.90(1H, brs).IR(KBr) cm⁻¹: 1652, 1612, 1519, 1439, 1291, 763. Mass m/z: 385(M⁺).

Example 191 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as a yellowoil (yield: 66.1%).

¹H NMR(400 MHz, CDCl₃)δ: 2.70–2.92(4H, m), 3.70–3.85(6H, m), 3.93(3H,s), 5.35(2H, s), 6.99–7.04(3H, m), 7.45–7.50(2H, m), 7.55(1H, d, J=8.3Hz), 7.63(1H, dd, J=12.4, 2.0 Hz), 7.90(1H, m). IR(Neat) cm⁻¹: 1652,1606, 1520, 1435, 1281, 762. Mass m/z: 385(M⁺—CH₂OH).

Example 192 Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one 1)Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand tert-butyl 1-piperazinecarboxylate were reacted to yield the titlecompound as a yellow oil (yield: 78.8%).

¹H NMR(400 MHz, CDCl₃)δ: 1.46(9H, s), 1.55–1.65(4H, m), 3.40–3.60(4H,m), 3.95(3H, s), 5.34(2H, s), 6.96–7.05(3H, m), 7.47–7.50(3H, m),7.41(1H, d, J=12.4 Hz), 7.74(1H, brs).

2) Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 20,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow crystallinepowder (yield: 63.4%).

Melting point: 142–143° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.50–2.60 (4H, m),2.96–3.02 (4H, m), 3.54 (2H, d, J=1.2 Hz), 3.95(3H, s), 5.34(2H, s),6.98–7.06(3H, m), 7.46–7.53(3H, m), 7.61(1H, dd, J=12.5, 2.2 Hz),7.74(1H, br.s). IR(KBr) cm⁻¹: 1652, 1609, 1523, 1437, 1290, 762. Massm/z: 426(M⁺).

Example 193 Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 76.9%).

Melting point: 153–156° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 3.30–3.75(10H, m),3.90(3H, s), 5.33(2H, s), 7.15–7.21(2H, m), 7.30(1H, m), 7.43–7.49(2H,m), 7.69–7.78(3H, m). IR(KBr) cm⁻¹: 1660, 1609, 1524, 1439, 1292, 766.

Example 194 Preparation of4-aminomethyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 24(1),2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield a crude product. Without purification, the crudeproduct was reacted further in accordance with the procedure of Example24 (2) to yield the title compound as a pale brown crystalline powder(yield: 50.4%).

Melting point: 145–149° C. ¹H NMR(400 MHz, CDCl₃)δ: 3.92(3H, s),3.94(2H, s), 5.31(2H, s), 6.95–7.03(3H, m), 7.40–7.52(3H, m), 7.60(1H,dd, J=12.5, 2.2 Hz), 7.75(1H, brs). IR(KBr) cm⁻¹: 3391, 1648, 1606,1519, 1437, 1292, 761. Mass m/z: 357(M⁺).

Example 195 Preparation of4-aminomethyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-aminomethyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a slightly-yellow crystallinepowder (yield: 72.5%).

Melting point: 210–214° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 3.91(3H, s),4.01(2H, s), 5.35(2H, s), 7.16–7.21(2H, m), 7.34(1H, dd, J=8.8, 8.8 Hz),7.45–7.49(2H, m), 7.68–7.78(2H, m), 8.29(1H, s). IR(KBr) cm⁻¹: 3429,1653, 1612, 1522, 1439, 1292, 764.

Example 196 Preparation of6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one 1)Preparation of6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one andthe mesylate derivative of 3-(4-fluorophenyl)-1-propanol {J. Med. Chem.,19, 461 (1976)} were reacted to yield the title compound as a yellow oil(yield: 90.1%). The mesylate derivative was prepared in accordance withthe procedure of Example 1(9).

¹H NMR(400 MHz, CDCl₃)δ: 2.16–2.26(2H, m), 2.71(2H, t, J=7.3 Hz),3.95(3H, s), 3.98(3H, s), 4.32(2H, t, J=7.3 Hz), 6.93–7.06(3H, m),7.14–7.18(2H, m), 7.49(1H, m), 7.60(1H, dd, J=13.2, 2.2 Hz), 8.17(1H,s).

2) Preparation of4-carboxy-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-one

Following the procedure of Example 1(7),6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methoxycarbonyl-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow powder (yield:89.2%).

Melting point: 185–187° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.20–2.30(2H, m),2.74(2H, t, J=7.3 Hz), 3.97(3H, s), 4.40(2H, t, J=7.3 Hz), 6.94–7.17(5H,m), 7.55(1H, d, J=8.5 Hz), 7.66(1H, dd, J=12.2, 2.2 Hz), 8.58(1H, s).

3) Preparation of6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow powder (yield:37.0%).

Melting point: 130–133° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.15–2.22(2H, m),2.71(2H, t, J=7.3 Hz), 3.95(3H, s), 4.27(2H, t, J=7.3 Hz), 4.70(2H, d,J=1.2 Hz), 6.93–7.06(3H, m), 7.14–7.18(2H, m), 7.50(1H, d, J=8.8 Hz),7.61(1H, dd, J=12.7, 2.2 Hz), 7.63(1H, s).

4) Preparation of6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow powder (yield:92.3%).

Melting point: 112–116° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.15–2.25(2H, m),2.71(2H, t, J=7.3 Hz), 3.17(3H, s), 3.95 (3H, s), 4.27(2H, t, J=7.3 Hz),5.25(2H, d, J=1.2 Hz), 6.93–7.05(3H, m), 7.14–7.18(2H, m), 7.49(1H, d,J=8.5 Hz), 7.61(1H, dd, J=13.4, 2.0 Hz), 7.72(1H, s).

5) Preparation of6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as ayellow oil (yield: 79.3%).

¹H NMR(400 MHz, CDCl₃)δ: 2.15–2.25(2H, m), 2.41(3H, s), 2.60–2.75(10H,m), 3.58(2H, s), 3.75(3H, s), 4.27(2H, t, J=7.3 Hz), 6.92–7.06(3H, m),7.14–7.18(2H, m), 7.51(1H, d, J=8.5 Hz), 7.60(1H, dd, J=12.4, 2.0 Hz),7.69(1H, s). IR(Neat) cm⁻¹: 1652, 1608, 1511, 1439, 1284, 758. Mass m/z:468(M⁺)

Example 197 Preparation of4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-one

Following the procedure of Example 7,6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand dimethylamine were reacted to yield the title compound as a paleyellow crystalline powder (yield: 61.8%).

Melting point: 97–100° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.15–2.25(2H, m),2.43(6H, s), 2.71(2H, t, J=7.3 Hz), 3.60(2H, s), 3.94(3H, s), 4.27(2H,t, J=7.3 Hz), 6.93–7.05(3H, m), 7.15–7.18(2H, m), 7.57(1H, d, J=8.5 Hz),7.64(1H, dd, J=12.6, 2.2 Hz), 7.90(1H, brs). IR(KBr) cm⁻¹: 1653, 1611,1510, 1436, 1296, 763. Mass m/z: 413(M⁺).

Example 198 Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as a yellowoil (yield: 67.3%).

¹H NMR(400 MHz, CDCl₃)δ: 2.14–2.22(2H, m), 2.70(2H, t, J=7.6 Hz),2.75–2.95(4H, m), 3.70–3.80(6H, m), 3.94(3H, s), 4.28(2H, t, J=7.6 Hz),6.93–7.05(3H, m), 7.15–7.18(2H, m), 7.56(1H, m), 7.63(1H, m), 7.85(1H,m). IR(Neat) cm⁻¹: 1645, 1601, 1510, 1439, 1277, 763. Mass m/z: 473(M⁺).

Example 199 Preparation of6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-(1-piperazinyl)methyl-2H-pyridazin-3-one 1)Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-one

Following the procedure of Example 1(10),6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand tert-butyl 1-piperazinecarboxylate were reacted to yield the titlecompound as a yellow oil (yield: 72.6%).

¹H NMR(400 MHz, CDCl₃)δ: 1.40(9H, s), 2.07–2.16(2H, m), 2.40–2.50(4H,m), 2.63(2H, t, J=7.6 Hz), 3.36–3.46(4H, m), 3.48(2H, brs), 3.88(3H, s),4.20(2H, t, J=7.6 Hz), 6.84–6.98(3H, m), 7.07–7.11(2H, m), 7.43(1H, d,J=8.1 Hz), 7.53(1H, d, J=12.4 Hz), 7.65(1H, brs).

2) Preparation of6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-(1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 20,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 97.2%).

¹H NMR(400 MHz, CDCl₃)δ: 2.12–2.22(2H, m), 2.50–2.60(4H, m), 2.71(2H, t,J=7.3 Hz), 2.92–3.02(4H, m), 3.53(2H, s), 3.95(3H, s), 4.27(2H, t, J=7.3Hz), 6.91–7.06(3H, m), 7.15–7.18(2H, m), 7.51(1H, d, J=8.8 Hz), 7.61(1H,dd, J=12.5, 2.2 Hz), 7.73(1H, s). IR(Neat) cm⁻¹: 1650, 1607, 1510, 1439,1275, 758. Mass m/z: 454(M⁺).

Example 200 Preparation of4-aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-one

Following the procedure of Example 24(1),6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield a crude product. Without purification, the crudeproduct was reacted in accordance with the procedure of Example 24(2) toyield the title compound as a pale yellow crystalline powder (yield:41.7%).

Melting point: 82–84° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.12–2.22(2H, m),2.70(2H, t, J=7.6 Hz), 3.89(2H, s), 3.94(3H, s), 4.27(2H, t, J=7.6 Hz),6.93–7.04(3H, m), 7.15–7.18(2H, m), 7.51(1H, d, J=7.3 Hz), 7.61(1H, dd,J=12.4, 2.0 Hz), 7.67(1H, s). IR(KBr) cm⁻¹: 3366, 1651, 1605, 1509,1436, 1273, 764. Mass m/z: 385(M⁺).

Example 201 Preparation of4-aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a slightly-yellow crystallinepowder (yield: 73.1%).

Melting point: 160–165° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 2.05–2.15(2H,m),2.66(2H, t, J=7.3 Hz), 3.92(3H, s), 3.99(2H, s), 4.19(2H, t, J=7.3 Hz),7.05–7.12(2H, m), 7.23–7.30(2H, m), 7.34(1H,dd, J=8.8, 8.8 Hz),7.66–7.76(2H, m), 8.25(1H,s). IR(KBr) cm⁻¹: 3430, 1652, 1515, 1436,1269, 763.

Example 202 Preparation of2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one 1)Preparation of2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and4-chlorobenzyl chloride were reacted to yield the title compound asyellow needles (yield: 97.6%).

Melting point: 170.5–171.1° C. ¹H NMR(400 MHz, CDCl₃)δ: 3.95(3H, s),3.99(3H, s), 5.38((2H, s), 7.03(1H, dd, J=8.5, 8.5 Hz), 7.31(2H, d,J=8.5 Hz), 7.47(2H, d, J=8.5 Hz), 7.49(1H, m), 7.60(1H, dd, J=12.2, 2.2Hz), 8.20(1H, s) IR(KBr) cm⁻¹: 1723, 1670, 1526, 1271, 1128. Mass m/z:402(M⁺), 404(M⁺).

2) Preparation of4-carboxy-2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(7),2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow crystallinepowder (yield: 96.0%).

Melting point: 228.3–229.1° C. ¹H NMR(400 MHz, CDCl₃)δ: 3.97(3H, s),5.46(2H, s), 7.07(1H, dd, J=8.5, 8.5 Hz), 7.35(2H, d, J=8.3 Hz),7.46(2H, d, J=8.3 Hz), 7.55(1H, d, J=8.4 Hz), 7.67(1H, dd, J=12.2, 2.2Hz), 8.61(1H, s). IR(KBr) cm⁻¹: 1745, 1635, 1456, 1447, 1431, 1298,1273. Mass m/z: 388(M⁺), 390(M⁺).

3) Preparation of2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow needles (yield:20.4%).

Melting point: 164.6–165.3° C. ¹H NMR(400 MHz, CDCl₃)δ: 3.94(3H, s),4.69(2H, s), 5.34 (2H, s), 7.01(1H, dd, J=8.5, 8.5 Hz), 7.30(2H, d,J=8.5 Hz), 7.42(2H, d, J=8.5 Hz), 7.50(1H, m), 7.63(1H, dd, J=12.4, 2.2Hz), 7.67(1H, s). IR(KBr) cm⁻¹: 3373, 1653, 1610, 1527, 1291, 1135. Massm/z: 374(M⁺), 376(M⁺).

4) Preparation of2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow needles (yield:81.6%).

Melting point: 156.5–157.4° C. ¹H NMR(400 MHz, CDCl₃)δ: 3.15(3H, s),3.95(3H, s), 5.22(2H, d, J=1.5 Hz), 5.35(2H, s), 7.03(1H, dd, J=8.5, 8.5Hz), 7.31(2H, d, J=8.5 Hz), 7.42(2H, d, J=8.5 Hz), 7.49(1H, m), 7.61(1H,dd, J=12.2, 2.2 Hz), 7.75(1H, s). IR(KBr) cm⁻¹: 1658, 1616, 1358, 1183,1017.

5) Preparation of2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as palebrown prisms (yield: 39.5%).

Melting point: 128.7–130.2° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.33(3H, s),2.52(4H, brs), 2.60(4H, brs), 3.55(2H, s), 3.95(3H, s), 5.34(2H, s),7.04(1H, dd, J=8.5, 8.5 Hz), 7.30(2H, d, J=8.5 Hz), 7.43(2H, d, J=8.5Hz), 7.51(1H, m), 7.60(1H, dd, J=12.4, 2.0 Hz), 7.73(1H, s). IR(KBr)cm⁻¹: 1652, 1607, 1524, 1516, 1438, 1288, 1135.

Example 203 Preparation of2-(4-chlorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 7,2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand dimethylamine were reacted to yield the title compound as aslightly-yellow crystalline powder (yield: 74.7%).

Melting point: 95.3–96.7° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.33(6H,s),3.47(2H, d, J=1.2 Hz), 3.94(3H, s), 5.34(2H, s), 7.01(1H, dd, J=8.5, 8.5Hz), 7.30(2H, d, J=8.5 Hz), 7.44(2H, d, J=8.5 Hz), 7.53(1H, ddd, J=8.5,2.0, 1.2 Hz), 7.62(1H, dd, J=12.4, 2.2 Hz), 7.74(1H, s). IR(KBr) cm⁻¹:1652, 1609, 1524, 1515, 1436, 1289, 1264, 1017. Mass m/z: 401(M⁺),403(M⁺).

Example 204 Preparation of2-(4-chlorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,2-(4-chlorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a slightly-yellow crystallinepowder (yield: 59.7%).

Melting point: 193.4–194.7° C. ¹H NMR(400 MHz, CD₃OD)δ: 2.96(6H, s),3.94(3H, s), 4.33(2H, s), 5.43(2H, s), 7.22(1H, dd, J=8.5, 8.5 Hz),7.36(2H, d, J=8.5 Hz), 7.46(2H, d, J=8.5 Hz), 7.67–7.72(2H, m), 8.20(1H,s). IR(KBr) cm⁻¹: 1655, 1616, 1529, 1327, 1279.

Example 205 Preparation of4-aminomethyl-2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one 1)Preparation of2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-phthalimidomethyl-2H-pyridazin-3-one

Following the procedure of Example 24(1),2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as slightly-yellow needles(yield: 75.4%).

Melting point: 212.5–213.9° C. ¹H NMR(400 MHz, CDCl₃)δ: 3.90(3H, s),4.88(2H, d, J=0.73 Hz), 5.35(2H, s), 6.95(1H, dd, J=8.5, 8.5 Hz),7.29(1H, s), 7.31(2H, d, J=8.5 Hz), 7.36(1H, m), 7.44(2H, d, J=8.5 Hz),7.47(1H, dd, J=12.2, 2.0 Hz), 7.76–7.81(2H, m), 7.89–7.94(2H, m).IR(KBr) cm⁻¹: 1773, 1713, 1651, 1610, 1522, 1439, 1419, 1393, 1300. Massm/z: 503(M⁺), 505 (M⁺).

2) Preparation of4-aminomethyl-2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 24(2),2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-phthalimidomethyl-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow needles (yield:48.8%).

Melting point: 128.5–131.4° C. ¹H NMR(400 MHz, CDCl₃)δ: 3.88(2H, s),3.94(3H, s), 5.34(2H, s), 7.02(1H, dd, J=8.5, 8.5 Hz), 7.30(2H, d, J=8.5Hz), 7.43(2H, d, J=8.5 Hz), 7.51(1H, ddd, J=8.5, 2.2, 1.2 Hz), 7.61(1H,dd, J=12.4, 2.2 Hz), 7.69(1H, t, J=1.2 Hz). IR(KBr) cm⁻¹: 3392, 1615,1604, 1520, 1434, 1292, 1133, 1018. Mass m/z: 373(M⁺), 375((M⁺).

Example 206 Preparation of4-aminomethyl-2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-aminomethyl-2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a slightly-yellow crystallinepowder (yield: 66.0%).

Melting point: 202.0–205.5° C. ¹H NMR(400 MHz, CD₃OD)δ: 3.94(3H, s),4.13(2H, s), 5.41(2H, s), 7.21(1H, dd, J=8.8, 8.8 Hz), 7.35(2H, d, J=8.5Hz), 7.46(2H, d, J=8.5 Hz), 7.65–7.71(2H, m), 8.08(1H, s). IR(KBr) cm⁻¹:2940, 1655, 1616, 1526, 1439, 1292.

Example 207 Preparation of2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one 1)Preparation of2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and3,4-difluorobenzyl bromide were reacted to yield the title compound as ayellow crystalline powder (yield: 92.1%).

Melting point: 144–148° C. ¹H NMR(400 MHz, CDCl₃)δ: 3.96(3H, s),3.97(3H, s), 5.35(2H, s), 7.04(1H, dd, J=8.5, 8.5 Hz), 7.12(1H, m),7.28(1H, m), 7.36(1H, m), 7.50(1H, m), 7.60(1H, dd, J=12.2, 1.5 Hz),8.21(1H, s). IR(KBr) cm⁻¹: 1756, 1656, 1609, 1518, 1439, 1239, 1293,1278, 1204. Mass m/z: 404(M⁺).

2) Preparation of4-carboxy-2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(7),2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow crystalline powder(yield: 97.6%).

Melting point: 196.4–197.0° C. ¹H NMR(400 MHz, CDCl₃)δ: 3.97(3H, s),5.44(2H, s), 7.07(1H, dd, J=8.5, 8.5 Hz), 7.17(1H, m), 7.27(1H, m),7.36(1H, ddd, J=8.1, 8.1, 2.2 Hz), 7.56(1H, m), 7.66(1H, dd, J=12.2, 2.2Hz), 8.61(1H, s), 13.83(1H, s). IR(KBr) cm⁻¹: 1757, 1636, 1567, 1518,1463, 1440, 1284. Mass m/z: 390(M⁺).

3) Preparation of2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as slightly-yellow needles(yield: 7.7%).

Melting point: 154.1–155.5° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.85(1H, t,J=5.6 Hz), 3.95(3H, s), 4.71(2H, d, J=5.6 Hz), 5.33(2H, s), 7.03(1H, dd,J=8.5, 8.5 Hz), 7.12(1H, m), 7.23(1H, m), 7.31(1H, ddd, J=11.0, 7.6, 2.2Hz), 7.51(1H, ddd, J=8.5, 2.2, 1.2 Hz), 7.61(1H, dd, J=12.4, 2.2 Hz),7.68(1H, t, J=1.2 Hz). IR(KBr) cm⁻¹: 3390, 1648, 1602, 1518, 1440, 1285,1141. Mass m/z: 376(M⁺).

4) Preparation of2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as slightly-yellow needles(yield: 91.5%).

Melting point: 145.6–146.6° C. ¹H NMR(400 MHz, CDCl₃)δ: 3.16(3H, s),3.96(3H, s), 5.26(2H, d, J=1.2 Hz), 5.32(2H, s), 7.04(1H, dd, J=8.5, 8.5Hz), 7.13(1H, m), 7.23(1H, m), 7.32(1H, m), 7.50(1H, m), 7.61(1H, dd,J=12.4, 2.2 Hz), 7.76(1H, t, J=1.2 Hz). IR (KBr) cm⁻¹: 1656, 1612, 1522,1440, 1352, 1277, 1163. Mass m/z: 454(M⁺).

5) Preparation of2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound asslightly-yellow needles (yield: 55.0%).

Melting point: 135.4–136.0° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.33(3H, s),2.51(4H, brs), 2.62(4H, brs), 3.56(2H, d, J=1.5 Hz), 3.95(3H, s),5.31(2H, s), 7.04(1H, dd, J=8.5, 8.5 Hz), 7.11(1H, m), 7.23(1H, m),7.32(1H, ddd, J=11.0, 7.6, 2.0 Hz), 7.52(1H, ddd, J=8.5, 2.2, 1.2 Hz),7.59(1H, dd, J=12.2, 2.2 Hz), 7.74(1H, t, J=1.2 Hz). IR(KBr) cm⁻¹: 1652,1608, 1522, 1437, 1291, 1273, 1139. Mass m/z: 458(M⁺).

Example 208 Preparation of2-(3,4-difluorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 7,2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand dimethylamine were reacted to yield the title compound asslightly-yellow needles (yield: 77.1%).

Melting point: 129.9–130.4° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.35(6H, s),3.49(2H, s), 3.95(3H, s), 5.32(2H, s), 7.02(1H, dd, J=8.5, 8.5 Hz),7.11(1H, m), 7.24(1H, m), 7.32(1H, ddd, J=11.0, 7.6, 2.2 Hz), 7.54(1H,ddd, J=8.5, 2.2, 1.2 Hz), 7.62(1H, dd, J=12.4, 2.2 Hz), 7.77(1H, s).IR(KBr) cm⁻¹: 1653, 1610, 1519, 1437, 1291, 1283, 1267, 1138, 1114. Massm/z: 403(M⁺).

Example 209 Preparation of2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one 1)Preparation of2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and4-chlorocinnamyl chloride were reacted to yield the title compound as apale yellow crystalline powder (yield: 51.1%).

Melting point: 117–119° C. ¹H NMR(400 MHz, CDCl₃)δ: 3.95(3H, s),3.98(3H, s), 5.02(2H, dd, J=6.8, 1.2 Hz), 6.43(1H, dt, J=15.9, 6.8 Hz),6.70(1H, d, J=15.9 Hz), 7.03(1H, dd, J=8.5, 8.5 Hz), 7.25(2H, d, J=8.8Hz), 7.31(2H, d, J=8.8 Hz), 7.50(1H, dt, J=8.5, 2.2 Hz), 7.62(1H, dd,J=12.2, 2.2 Hz), 8.22(1H,s). IR(KBr) cm⁻¹: 1724, 1709, 1667, 1506, 1291,1236, 1126, 831. Mass m/z: 412(M⁺), 414(M⁺).

2) Preparation of4-carboxy-2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(7),2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow crystallinepowder (yield: 98.2%).

Melting point: 217.2–218.5° C. ¹H NMR(400 MHz, CDCl₃)δ: 3.97(3H, s),5.10(2H, d, J=6.8 Hz), 6.39(1H, dt, J=15.9, 6.8 Hz), 6.75(1H, d, J=15.9Hz), 7.06(1H, dd, J=8.5, 8.5 Hz), 7.30(2H, d, J=8.5 Hz), 7.34(2H, d,J=8.5 Hz), 7.57(1H, m), 7.69(1H, dd, J=12.2, 2.2 Hz), 8.63(1H, s),13.99(1H, s). IR(KBr) cm⁻¹: 3059, 1744, 1629, 1523, 1480, 1438, 1426,1296, 1272. Mass m/z: 414(M⁺), 416(M⁺).

3) Preparation of2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow crystals (yield:17.0%).

Melting point: 158.2–160.5° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.95(1H, t,J=5.9 Hz), 3.94(3H, s), 4.73(2H, dd, J=5.9, 1.2 Hz), 4.98(2H, dd, J=6.6,1.2 Hz), 6.40(1H, dt, J=15.9, 6.6 Hz), 6.67(1H, d, J=15.9 Hz), 7.02(1H,dd, J=8.5, 8.5 Hz), 7.27 (2H, d, J=8.5 Hz), 7.32 (2H, d, J=8.5 Hz), 7.51(1H, ddd, J=8.8, 2.2, 1.2 Hz), 7.63(1H, dd, J=12.4, 2.2 Hz), 7.67(1H, t,J=1.2 Hz). IR(KBr) cm⁻¹: 3392, 1648, 1603, 1523, 1440, 1284, 1273, 1140.Mass m/z: 400(M⁺), 402(M⁺).

4) Preparation of2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow needles (yield:90.7%).

Melting point: 135.8–136.4° C. ¹H NMR(400 MHz, CDCl₃)δ: 3.17(3H, s),3.95(3H, s), 4.98(2H, dd, J=6.6, 0.98 Hz), 5.28(2H, d, J=1.5 Hz),6.39(1H, dt, J=15.9, 6.6 Hz), 6.67(1H, d, J=15.9 Hz), 7.03(1H, dd,J=8.5, 8.5 Hz), 7.27(2H, d, J=8.5 Hz), 7.32(2H, d, J=8.5 Hz), 7.50(1H,m), 7.62(1H, dd, J=12.2, 2.2 Hz), 7.77(1H, t, J=1.2 Hz). IR(KBr) cm⁻¹:1660, 1615, 1523, 1436, 1360, 1335, 1287, 1273, 1179. Mass m/z: 478(M⁺),480(M⁺).

5) Preparation of2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as palebrown needles (yield: 66.3%).

Melting point: 123.9–125.5° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.33(3H, s),2.52(4H, brs), 2.62(4H, brs), 3.58(2H, d, J=1.2 Hz), 3.95(3H, s),4.98(2H, dd, J=6.8, 1.2 Hz), 6.41(1H, dt, J=15.9, 6.8 Hz), 6.66(1H, d,J=15.9 Hz), 7.04(1H, dd, J=8.5, 8.5 Hz), 7.26(2H, d, J=8.5 Hz), 7.32(2H,d, J=8.5 Hz), 7.53 (1H, ddd, J=8.5, 2.0, 1.2 Hz), 7.62(1H, dd, J=12.4,2.2 Hz), 7.75(1H, t, J=1.2 Hz). IR(KBr) cm⁻¹: 1647, 1606, 1522, 1439,1282, 1270. Mass m/z: 482(M⁺), 484(M⁺).

Example 210 Preparation of2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-[4-(2-hydroxyethyl)-1-piperazinyl]methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand 1-piperazineethanol were reacted to yield the title compound asslightly-yellow needles (yield: 65.1%).

Melting point: 133.1–134.9° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.57–2.62(11H,m), 3.58(2H, d,J=1.2 Hz), 3.63(2H, t, J=5.4 Hz), 3.94(3H, s), 4.97(2H,d, J=6.6 Hz), 6.41(1H, dt, J=15.9, 6.6 Hz), 6.67(1H, d, J=15.9 Hz),7.03(1H, dd, J=8.5, 8.5 Hz), 7.26(2H, d, J=8.5 Hz), 7.32(2H, d, J=8.5Hz), 7.53(1H, m), 7.61(1H, dd, J=12.4, 2.2 Hz), 7.75(1H, s). IR(KBr)cm⁻¹: 3451, 1647, 1605, 1523, 1438, 1285, 1274, 1137. Mass m/z: 478(M⁺),480(M⁺).

Example 211 Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(4-methyl-1-piperazinyl)propyl]-2H-pyridazin-3-one 1)Preparation of4-bromomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

2-Cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one(185 mg, 0.61 mmol), carbon tetrabromide (404 mg, 1.2 mmol) and pyridine(48 mg, 0.61 mmol) were dissolved in tetrahydrofuran (3 mL), and underice-cold stirring, a solution of triphenylphosphine (319 mg, 1.2 mmol)in tetrahydrofuran (3 mL) was added. Under ice cooling, the mixture wasstirred for 1 hour, and further stirred at room temperature. Insolublematerials were filtered off, the solvent was distilled off under reducedpressure, and the residue was isolated and purified by columnchromatography on silica gel (hexane/ethyl acetate=2/1) to yield thetitle compound as a yellow powder (yield: 155 mg, 69.5%).

¹H NMR(400 MHz, CDCl₃)δ: 0.45–0.60(4H, m), 1.58(1H, m), 3.95(3H, s),4.12(2H, d, J=7.3 Hz), 4.49(2H, s), 7.03(1H, dd, J=8.5, 8.5 Hz),7.50(1H, m), 7.60(1H, dd, J=13.4, 2.2 Hz), 7.77(1H, s).

2) Preparation of2-cyclopropylmethyl-4-[2,2-di(tert-butoxycarbonyl)ethyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

After 55% sodium hydride (322 mg, 7.38 mmol) was added to a solution ofdi-tert-butyl malonate (970 mg, 4.48 mmol) in N,N-dimethylformamide (10mL),4-bromomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one(1.8 g, 4.90 mmol) was added under ice-cold stirring. The reactionmixture was stirred at room temperature for 1 hour, poured into water,and extracted with ethyl acetate. The extract was washed with brine anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure. The residue was isolated and purified by columnchromatography on silica gel (hexane/ethyl acetate=3/1) to yield thetitle compound as a yellow powder (yield: 1.39 mg, 61.8%).

¹H NMR(400 MHz, CDCl₃)δ: 0.44–0.50(2H, m), 0.50–0.58(2H, m), 1.41(18H,s), 1.56(1H, m), 3.12(2H, d, J=7.8 Hz), 3.87(1H, t, J=7.8 Hz), 3.94(3H,s), 4.09(2H, d, J=7.8 Hz), 7.01 (1H, dd, J=8.5, 8.5 Hz), 7.43(1H, d,J=8.5 Hz), 7.50(1H, s), 7.57(1H, dd, J=12.4, 2.2 Hz).

3) Preparation of4-(2-carboxyethyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Trifluoroacetic acid (21 mL) was added to2-cyclopropylmethyl-4-[2,2-di(tert-butoxycarbonyl)ethyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one(1.39 g, 2.77 mmol), and the mixture was stirred at room temperature for30 minutes. The solvent was distilled off under reduced pressure, andtoluene was added further, followed by azeotropic boiling. The residuewas heated at 190 to 200° C. for 30 minutes under a nitrogen atmosphereto yield the title compound as a pale brown powder (yield: 907 mg,94.7%).

¹H NMR(400 MHz, CDCl₃)δ: 0.45–0.50(2H, m), 0.50–0.60(2H, m), 1.41(1H,m), 2.80(2H, t, J=7.1 Hz), 2.97(2H, t, J=7.1 Hz), 3.94(3H, s), 4.10(2H,d, J=7.3 Hz), 7.02(1H, dd, J=8.5, 8.5 Hz), 7.47(1H, d, J=8.5 Hz),7.55(1H, s), 7.59(1H, dd, J=12.4, 2.2 Hz).

4) Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-hydroxypropyl)-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-(2-carboxyethyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a brown oil (yield: 82.9%).

¹H NMR(400 MHz, CDCl₃)δ: 0.44–0.52(2H, m), 0.52–0.60(2H, m), 1.42(1H,m), 1.88–1.94(2H, m), 2.81(2H, t, J=6.1 Hz), 3.63(2H, t, J=5.9 Hz),3.95(3H, s), 4.12(2H, d, J=7.3 Hz), 7.02(1H, dd, J=8.5, 8.5 Hz),7.50(1H, m), 7.52(1H, s), 7.60(1H, dd, J=12.4, 2.2 Hz).

5) Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-hydroxypropyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a pale brown powder (yield:82.0%).

¹H NMR(400 MHz, CDCl₃)δ: 0.44–0.51(2H, m), 0.51–0.60(2H, m), 1.41(1H,m), 2.13–2.21(2H, m), 2.80(2H, t, J=7.1 Hz), 3.04(3H, s), 3.94(3H, s),4.09(2H, d, J=7.3 Hz), 4.31(2H, t, J=6.1 Hz), 7.02(1H, dd, J=8.5, 8.5Hz), 7.49(1H, d, J=8.5 Hz), 7.53(1H, s), 7.61(1H, dd, J=12.4, 2.2 Hz).

6) Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(4-methyl-1-piperazinyl)propyl]-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as ayellow oil (yield: 62.0%).

¹H NMR(400 MHz, CDCl₃)δ: 0.44–0.50(2H, m), 0.50–0.60(2H, m), 1.41(1H,m), 1.90–2.00(2H, m), 2.45(3H, s), 2.50–3.00(12H, m), 3.94(3H, s),4.08(2H, d, J=7.3 Hz), 7.02(1H, dd, J=8.5, 8.5 Hz), 7.48(1H, s),7.50(1H, d, J=8.5 Hz), 7.70(1H, dd, J=12.3, 2.0 Hz). IR(Neat) cm⁻¹:1648, 1607, 1524, 1286, 1122, 1022, 755. Mass m/z: 414(M⁺).

Example 212 Preparation of2-cyclopropylmethyl-4-(3-dimethylaminopropyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 7,2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-oneand dimethylamine were reacted to yield the title compound as a yellowoil (yield: 64.7%).

¹H NMR(400 MHz, CDCl₃)δ: 0.44–0.50(2H, m), 0.53–0.60(2H, m), 1.40(1H,m), 2.24–2.35(2H, m), 2.75–2.80(2H, m), 2.79(6H, s), 3.03(2H, t, J=7.3Hz), 3.94(3H, s), 4.08(2H, d, J=7.1 Hz), 7.04(1H, dd, J=8.5, 8.5 Hz),7.57(1H, d, J=8.5 Hz), 7.65(1H, dd, J=12.4, 2.2 Hz), 7.72 (1H, s).IR(Neat) cm⁻¹: 1649, 1608, 1524, 1288, 1122, 1022, 761. Mass m/z:359(M⁺).

Example 213 Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one 1)Preparation of2-cyclopropylmethyl-4-[3-(4-tert-butoxycarbonyl-1-piperazinyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-oneand tert-butyl 1-piperazinecarboxylate were reacted to yield the titlecompound as a yellow oil (yield: 76.9%).

¹H NMR(400 MHz, CDCl₃)δ: 0.44–0.50(2H, m), 0.52–0.60(2H, m), 1.44(1H,m), 1.46(9H, s), 2.00–2.40(2H, m), 2.50–2.80(6H, m), 3.50–3.75(6H, m),3.94(3H, s), 4.08(2H, d, J=7.1 Hz), 7.02(1H, dd, J=8.5, 8.5 Hz),7.47–7.65(3H, m).

2) Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one

Following the procedure of Example 20,2-cyclopropylmethyl-4-[3-(4-tert-butoxycarbonyl-1-piperazinyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 78.9%).

¹H NMR(400 MHz, CDCl₃)δ: 0.43–0.50(2H, m), 0.50–0.59(2H, m), 1.42(1H,m), 1.82–1.92(2H, m), 2.40–2.50(6H, m), 2.68(2H, t, J=7.6 Hz),2.93–2.95(4H, m), 3.94(3H, s), 4.08(2H, d, J=7.3 Hz), 7.01(1H, dd,J=8.5, 8.5 Hz), 7.45(1H, s), 7.48(1H, d, J=8.5 Hz), 7.59(1H, dd, J=11.4,2.0 Hz). IR(Neat) cm⁻¹: 1648, 1607, 1523, 1288, 1122, 1023, 760. Massm/z: 400(M⁺).

Example 214 Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a slightly-yellow crystallinepowder (yield: 83.1%).

Melting point: 174–178° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.39–0.45(2H, m),0.45–0.55(2H, m), 1.32(1H, m), 2.00–2.25(2H, m), 2.62–2.66 (2H, m),3.20–3.85(10H, m), 3.90(3H, s), 4.01(2H, d, J=7.1 Hz), 7.28(1H, dd,J=8.8, 8.8 Hz), 7.72–7.80(2H, m), 7.96(1H, s). IR(KBr) cm⁻¹: 1647, 1604,1523, 1297, 1123, 1020, 762.

Example 215 Preparation of4-[3-[N,N-bis(2-hydroxyethyl)amino]propyl]-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as a yellowoil (yield: 13.1%).

¹H NMR(400 MHz, CDCl₃)δ: 0.44–0.50(2H, m), 0.50–0.60(2H, m), 1.41(1H,m), 2.10–2.20(2H, m), 2.76(2H, t, J=7.3 Hz), 3.00–3.15(6H, m),3.87–3.92(4H, m), 3.94(3H, s), 4.08(2H, d, J=7.3 Hz), 7.02(1H, dd,J=8.5, 8.5 Hz), 7.53(1H, d, J=8.5 Hz), 7.60(1H, s), 7.62(1H, dd, J=12.4,2.2 Hz). IR(Neat) cm⁻¹: 1645, 1602, 1524, 1288, 1123, 1024, 756. Massm/z: 400(M⁺—CH₂OH).

Example 216 Preparation of4-(3-aminopropyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 24(1),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-onewas reacted to yield a crude product. Without purification, the crudeproduct was reacted further in accordance with the procedure of Example24(2) to yield the title compound as a yellow oil (yield: 67.8%).

¹H NMR(400 MHz, CDCl₃)δ: 0.44–0.50(2H, m), 0.50–0.60(2H, m), 1.41(1H,m), 1.84–1.96(2H, m), 2.67–2.80(4H, m), 2.87(2H, t, J=6.1 Hz), 3.94(3H,s), 4.08(2H, d, J=7.3 Hz), 7.01(1H, dd, J=8.5, 8.5 Hz), 7.49(1H, d,J=8.5 Hz), 7.50(1H, s), 7.59(1H, dd, J=12.4, 2.2 Hz). IR(Neat) cm⁻¹:3370, 1648, 1606, 1523, 1289, 1122, 1023, 760. Mass m/z: 331(M⁺).

Example 217 Preparation of4-(3-aminopropyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-(3-aminopropyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a slightly-yellow crystallinepowder (yield: 70.6%).

Melting point: 183–185° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 0.40–0.45(2H, m),0.45–0.55(2H, m), 1.32(1H, m), 1.88–1.93(2H, m), 2.64(2H, t, J=7.3 Hz),2.78–2.88(2H, m), 3.90(3H, s), 4.00(2H, d, J=7.3 Hz), 7.28(1H, dd,J=8.5, 8.5 Hz), 7.70–7.78(2H, m), 7.96(1H, s). IR(KBr) cm⁻¹: 3437, 1648,1608, 1526, 1273, 1122, 1021, 762.

Referential Example Preparation of 3-(2,6-dichlorophenyl)-1-propanolmethanesulfonate 1) Preparation of ethyl 2,6-dichlorocinnamate

To a solution of 2,6-dichlorobenzaldehyde (350 mg, 2.0 mmol) andtriethyl phosphonoacetate (448 mg, 2.6 mmol) in THF (5 mL), potassiumtert-butoxide (291 mg, 2.6 mmol) was added under ice cooling, and at thesame temperature, the mixture was stirred for 2 hours. A saturatedaqueous solution of ammonium chloride was added to the reaction mixture,followed by extraction with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate and then concentrated under reducedpressure. Further, the residue was purified by column chromatography onsilica gel (hexane/ethyl acetate=50/1) to yield the title compound as acolorless syrupy substance (yield: 65.1%).

¹H NMR(400 MHz, CDCl₃)δ: 1.35(3H, t, J=7.2 Hz), 4.30(2H, q, J=7.2 Hz),6.59(1H, d, J=16.4 Hz), 7.19(1H, t, J=8.0 Hz), 7.36(2H, t, J=8.0 Hz),7.79(1H, d, J=16.4 Hz).

2) Preparation of 3-(2,6-dichlorophenyl)-1-propanol

Lithium aluminum hydride (98.8 mg, 2.60 mmol) was added to THF (5 mL),and under ice-cold stirring, a solution of ethyl 2,6-dichlorocinnamate(319 mg, 1.30 mmol) in THF (5 mL) was added dropwise. The mixture wasthen stirred at room temperature for 30 minutes. A small amount of asaturated aqueous solution of ammonium chloride was added to thereaction mixture, followed by drying over anhydrous magnesium sulfate.Subsequent to filtration through Celite, the mixture was concentratedunder reduced pressure and further, purified by column chromatography onsilica gel (hexane/ethyl acetate=10/1) to yield the title compound as apale yellow syrupy substance (yield: 46.9%).

¹H NMR(400 MHz, CDCl₃)δ: 1.83–1.93(2H, m), 3.02(2H, t, J=7.8 Hz),3.73(2H, t, J=6.3 Hz), 7.09(1H, t, J=8.3 Hz), 7.27(2H, d, J=8.3 Hz).

3) Preparation of 3-(2,6-dichlorophenyl)-1-propanol methanesulfonate

To a solution of 3-(2,6-dichlorophenyl)-1-propanol (125 mg, 0.61 mmol)and triethylamine (123 mg, 1.22 mmol) in methylene chloride (3 mL),methanesulfonyl chloride (105 mg, 0.915 mmol) was added under icecooling, followed by stirring at room temperature for 2 hours. Brine wasadded to the reaction mixture. The organic layer was allowed toseparate, was collected, and was then dried over anhydrous sodiumsulfate. Subsequent to concentration under reduced pressure, the residuewas purified by column chromatography on silica gel (hexane/ethylacetate=10/1) to yield the title compound as a pale yellow syrupysubstance (yield: quantitative).

¹H NMR(400 MHz, CDCl₃)δ: 2.02–2.12(2H, m), 3.00–3.10(5H, m), 4.32(2H, t,J=6.3 Hz), 7.10(1H, t, J=8.3 Hz), 7.28(2H, d, J=8.3 Hz).

Example 218 Preparation of2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one 1)Preparation of4-carboxy-2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and3-(4-chlorophenyl)-1-propanol methanesulfonate were reacted to yield acrude product. Without purification, the crude product was reactedfurther in accordance with the procedure of Example 1(7) to yield thetitle compound as a yellow crystalline powder (yield: 80.8%).

Melting point: 120–123° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.22–2.32(2H, m),2.37(3H, d, J=1.7 Hz), 2.74(2H, t, J=7.3 Hz), 4.06 (2H, t, J=7.3 Hz),7.13 (2H, d, J=8.5 Hz), 7.14 (1H, m), 7.24(2H, d, J=8.5 Hz),7.60–7.70(2H, m), 8.59(1H, s).

2) Preparation of2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 25.2%).

¹H NMR(400 MHz, CDCl₃)δ: 2.16–2.24(2H, m), 2.35(3H, d, J=1.7 Hz),2.70(2H, t, J=7.3 Hz), 4.28(2H, t, J=7.3 Hz), 4.69(2H, d, J=1.2 Hz),7.09(1H, m), 7.14(2H, d, J=8.3 Hz), 7.23(2H, d, J=8.3 Hz), 7.55–7.64(2H,m), 7.64(1H, s).

3) Preparation of2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 89.8%).

¹H NMR(400 MHz, CDCl₃)δ: 2.16–2.24(2H, m), 2.36(3H, d, J=2.0 Hz),2.71(2H, t, J=7.3 Hz), 3.17(3H, s), 4.28(2H, t, J=7.3 Hz), 5.25(2H, d,J=1.5 Hz), 7.10(1H, m), 7.13(2H, d, J=8.5 Hz), 7.23(2H, d, J=8.5 Hz),7.55–7.66(2H, m), 7.73(1H, t, J=1.2 Hz).

4) Preparation of2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 59.2%).

¹H NMR(400 MHz, CDCl₃)δ: 2.16–2.23(2H, m), 2.36(3H, s), 2.37(3H, d,J=1.7 Hz), 2.55–2.73(10H, m), 3.56(2H, d, J=1.5 Hz), 4.27(2H, t, J=7.3Hz), 7.10(1H, m), 7.14(2H, d, J=8.5 Hz), 7.21(2H, d, J=8.5 Hz),7.55–7.65(2H, m), 7.69(1H, s). IR(Neat) cm⁻¹: 1652, 1608, 1493, 1239,1015, 755. Mass m/z: 468(M⁺), 470(M⁺).

Example 219 Preparation of2-[3-(2-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one 1)Preparation of4-carboxy-2-[3-(2-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and3-(2-chlorophenyl)-1-propanol methanesulfonate were reacted to yield acrude product. Without purification, the crude product was reactedfurther in accordance with the procedure of Example 1(7) to yield thetitle compound as a yellow crystalline powder (76.8%).

Melting point: 156–159° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.27–2.35(2H, m),2.37(3H, d, J=2.0 Hz), 2.88(2H, t, J=7.3 Hz), 4.45(2H, t, J=7.3 Hz),7.11–7.34(5H, m), 7.63–7.72(2H, m), 8.60(1H, s).

2) Preparation of2-[3-(2-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-[3-(2-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 38.9%).

¹H NMR(400 MHz, CDCl₃)δ: 2.20–2.27(2H, m), 2.35(3H, d, J=2.0 Hz),2.85(2H, t, J=7.3 Hz), 4.33(2H, t, J=7.3 Hz), 4.71(2H, d, J=1.2 Hz),7.06–7.34(5H, m), 7.56–7.64(2H,m), 7.65(1H, s).

3) Preparation of2-[3-(2-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-[3-(2-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a brown oil (yield: 92.5%).

¹H NMR(400 MHz, CDCl₃)δ: 2.20–2.27(2H, m), 2.36(3H, d, J=1.7 Hz),2.85(2H, t, J=7.1 Hz), 3.17(3H, s), 4.33(2H, t, J=7.1 Hz), 5.27(2H, d,J=1.2 Hz), 7.07–7.34(5H, m), 7.56–7.65(2H, m), 7.75(1H, s).

4) Preparation of2-[3-(2-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-[3-(2-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 66.7%).

¹H NMR(400 MHz, CDCl₃)δ: 2.17–2.26(2H, m), 2.34(3H, s), 2.36(3H, d,J=2.0 Hz), 2.50–2.68(8H, m), 2.85(2H, t, J=7.6 Hz), 3.58(2H, d, J=1.5Hz), 4.32(2H, t, J=7.3 Hz), 7.07–7.35(5H, m), 7.58(1H, m), 7.65(1H, m),7.72(1H, s). IR(Neat) cm⁻¹: 1652, 1608, 1456, 1238, 1015, 753. Mass m/z:468(M⁺), 470(M⁺).

Example 220 Preparation of2-[3-(2-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-[3-(2-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless flakes (yield:62.0%).

Melting point: 230–236° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 2.08–2.16(2H, m),2.32(3H, s), 2.79(2H, t, J=7.6 Hz), 2.81(3H, s), 3.20–3.63(10H, m),4.23(2H, t, J=7.6 Hz), 7.20–7.32(3H, m), 7.38–7.39(2H, m), 7.41(1H, s),7.71(1H, m), 8.27(1H, brs). IR(KBr) cm⁻¹: 3301, 2984, 1651, 1608.

Example 221 Preparation of2-[3-(3-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one 1)Preparation of4-carboxy-2-[3-(3-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and3-(3-chlorophenyl)-1-propanol methanesulfonate were reacted to yield acrude product. Without purification, the crude product was reactedfurther in accordance with the procedure of Example 1(7) to yield thetitle compound as a yellow crystalline powder (79.1%).

Melting point: 117–120° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.26–2.33(2H, m),2.37(3H, d, J=2.0 Hz), 2.75(2H, t, J=7.3 Hz), 4.42(2H, t, J=7.3 Hz),7.06–7.22(5H, m), 7.63–7.70(2H, m), 8.58(1H, s).

2) Preparation of2-[3-(3-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-[3-(3-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 51.8%).

¹H NMR(400 MHz, CDCl₃)δ: 2.18–2.26(2H, m), 2.36(3H, d, J=2.0 Hz),2.72(2H, t, J=7.6 Hz), 4.30(2H, t, J=7.3 Hz), 4.70(2H, s), 7.07–7.22(5H,m), 7.55–7.63(2H,m), 7.64(1H, s).

3) Preparation of2-[3-(3-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-[3-(3-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a brown oil (yield: 86.7%).

¹H NMR(400 MHz, CDCl₃)δ: 2.20–2.26(2H, m), 2.36(3H, d, J=1.7 Hz),2.71(2H, t, J=7.6 Hz), 3.17(3H, s), 4.30(2H, t, J=7.1 Hz), 5.25(2H, d,J=1.2 Hz), 7.07–7.22(5H, m), 7.55–7.64(2H, m), 7.73(1H, s).

4) Preparation of2-[3-(3-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-[3-(3-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 56.2%).

¹H NMR(400 MHz, CDCl₃)δ: 2.17–2.25(2H, m), 2.36(3H, s), 2.37(3H, s),2.55–2.68(8H, m), 2.71(2H, t, J=7.6 Hz), 3.57(2H, d, J=1.2 Hz), 4.28(2H,t, J=7.3 Hz), 7.07–7.22(5H, m), 7.57(1H, m), 7.64(1H, m), 7.70(1H, s).IR(Neat) cm⁻¹: 1652, 1607, 1456, 1239, 1015, 755. Mass m/z: 468(M⁺),470(M⁺).

Example 222 Preparation of2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one 1)Preparation of4-carboxy-2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and4-chlorobenzyl chloride were reacted to yield a crude product. Withoutpurification, the crude product was reacted further in accordance withthe procedure of Example 1(7) to yield the title compound as a paleyellow crystalline powder (46.5%).

Melting point: 219.5–220.5° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.37(3H, d,J=1.7 Hz), 5.48(2H, s), 7.14(1H, dd, J=8.8, 8.8 Hz), 7.35(2H, d, J=8.3Hz), 7.46(2H, d, J=8.3 Hz), 7.63–7.70(2H, m), 8.62(1H, s), 13.90(1H,brs). IR(KBr) cm⁻¹: 1745, 1634, 1561, 1493, 1475, 1245, 806.

2) Preparation of2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a slightly-yellow needles(yield: 23.3%).

Melting point: 157.1–158.3° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.35(3H, d,J=2.0 Hz), 4.70(2H, s), 5.36(2H, s), 7.09(1H, dd, J=8.8, 8.8 Hz),7.31(2H, d, J=8.3 Hz), 7.42(2H, d, J=8.3 Hz), 7.56–7.65(2H, m), 7.67(1H,s). IR(KBr) cm⁻¹: 3422, 1645, 1604, 1508, 1459, 1239, 1091, 819. Massm/z: 358(M⁺), 360(M⁺).

3) Preparation of2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow needles (yield:89.1%).

Melting point: 131.8–132.7° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.36(3H, d,J=2.0 Hz), 3.15(3H, s), 5.25(2H, d, J=1.5 Hz), 5.36(2H, s), 7.10(1H, dd,J=9.0, 9.0 Hz), 7.31(2H, d, J=8.3 Hz), 7.42(2H, d, J=8.3 Hz),7.55–7.63(2H, m), 7.76(1H, s). IR(KBr) cm⁻¹: 1661, 1618, 1352, 1165,877. Mass m/z: 436(M⁺), 438(M⁺).

4) Preparation of2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow needles (yield:58.7%).

Melting point: 133.3–133.8° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.35(3H, d,J=2.0 Hz), 2.43(3H, s), 2.70(8H, brs), 3.58(2H, d, J=1.2 Hz), 5.35(2H,s), 7.10(1H, dd, J=8.8, 8.8 Hz), 7.30(2H, d, J=8.3 Hz), 7.43(2H, d,J=8.3 Hz), 7.59(1H, m), 7.62(1H, dd, J=7.3, 2.0 Hz), 7.71(1H, s).IR(KBr) cm⁻¹: 2798, 1655, 1606, 1492, 1235, 1166, 1104. Mass m/z:440(M⁺), 442(M⁺).

Example 223 Preparation of2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 88.5%).

Melting point: 246.4–249.7° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:2.31(3H, s), 2.82(3H, s), 3.17(8H, brs), 4.09(2H, brs), 5.36(2H, s),7.30(1H, dd, J=9.0, 9.0 Hz), 7.42(4H, s), 7.76(1H, m), 7.84(1H, dd,J=7.3, 2.2 Hz), 8.34(1H, s). IR(KBr) cm⁻¹: 1654, 1612, 1505. Mass m/z:440(M⁺), 442(M⁺).

Example 224 Preparation of2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one 1)Preparation of4-carboxy-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and2-chlorobenzyl chloride were reacted to yield a crude product. Withoutpurification, the crude product was reacted further in accordance withthe procedure of Example 1(7) to yield the title compound as pale yellowneedles (76.4%).

Melting point: 185.1–185.9° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.34(3H, s),5.67(2H, s), 7.10(1H, dd, J=8.8, 8.8 Hz), 7.25–7.35(3H, m), 7.46(1H, m),7.62(1H, m), 7.65(1H, d, J=7.3 Hz), 8.66(1H, s), 13.92(1H, s). IR(KBr)cm⁻¹: 1751, 1638, 1565, 1472, 1239. Mass m/z: 372(M⁺), 374(M⁺).

2) Preparation of2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow needles (yield:21.3%).

Melting point: 149.0–149.7° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.32(3H, d,J=1.7 Hz), 4.73(2H, d, J=1.2 Hz), 5.55(2H, s), 7.06(1H, dd, J=8.8, 8.8Hz), 7.15–7.26(3H, m), 7.40(1H, m), 7.57(1H, m), 7.62(1H, dd, J=7.3, 2.2Hz), 7.73(1H, t, J=1.2 Hz). IR(KBr) cm⁻¹: 3409, 1668, 1652, 1506, 1446,1241. Mass m/z: 358(M⁺), 360(M⁺).

3) Preparation of2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as slightly-yellow needles(yield: 82.1%).

Melting point: 142.3–143.0° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.33(3H, d,J=1.7 Hz), 3.16(3H, s), 5.29(2H, d, J=1.2 Hz), 5.56(2H, s), 7.07(1H, dd,J=8.8, 8.8 Hz), 7.19–7.28(3H, m), 7.42(1H, m), 7.56(1H, m), 7.60(1H, dd,J=7.3, 2.2 Hz), 7.81(1H, s). IR(KBr) cm⁻¹: 1659, 1618, 1613, 1355, 1166,1034. Mass m/z: 436(M⁺), 438(M⁺).

4) Preparation of2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow needles (yield:53.4%).

Melting point: 149.7–150.9° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.33(3H, d,J=1.7 Hz), 2.38(3H, s), 2.61(4H, brs), 2.68(4H, brs), 3.61(2H, d, J=1.5Hz), 5.55(2H, s), 7.06(1H, dd, J=8.8, 8.8 Hz), 7.17–7.26(3H, m), 7.41(1H, m), 7.56(1H, m), 7.62 (1H, dd, J=7.1, 2.0 Hz), 7.77(1H, s). IR(KBr)cm⁻¹: 2792, 1659, 1618, 1611, 1504, 1285, 1237, 1170. Mass m/z: 440(M⁺),442(M⁺).

Example 225 Preparation of2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as a slightly-yellow crystallinepowder (yield: 78.1%).

Melting point: 191–202° C. (dec.) ¹H NMR(400 MHz, CD₃OD)δ: 2.31(3H, d,J=1.7 Hz), 3.01(3H, s), 3.68(8H, brs), 4.40(2H, s), 5.57(2H, s),7.12(1H, dd, J=8.8, 8.8 Hz), 7.27–7.35(3H, m), 7.46(1H, m), 7.72(1H, m),7.77(1H, d, J=7.1 Hz), 8.40(1H, s). IR(KBr) cm⁻¹: 1656, 1612, 1504,1446, 1128. Mass m/z: 440(M⁺), 442(M⁺).

Example 226 Preparation of2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-[3-(4-methyl-1-piperazinyl)propyl]-2H-pyridazin-3-one 1)Preparation of4-bromomethyl-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 211(1),2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as slightly-yellow needles(yield: 46.2%).

Melting point: 113–115° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.33(3H, d, J=2.0Hz), 4.50(2H, d, J=0.98 Hz), 5.75(2H, s), 7.07(1H, dd, J=8.8, 8.8 Hz),7.21–7.25(3H, m), 7.42(1H, m), 7.51–7.61(2H,m), 7.83(1H, t, J=0.98 Hz).

2) Preparation of2-(2-chlorobenzyl)-4-[2,2-di(tert-butoxycarbonyl)ethyl]-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 211(2),4-bromomethyl-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 88.4%).

¹H NMR(400 MHz, CDCl₃)δ: 1.41(18H, s), 2.31(3H, d, J=1.7 Hz), 3.14(2H,d, J=7.8 Hz), 3.87(1H, t, J=7.8 Hz), 5.54(2H, s), 7.04(1H, dd, J=8.8,8.8 Hz), 7.14–7.24(3H, m), 7.40(1H, m), 7.48–7.56(2H, m), 7.57(1H, s).

3) Preparation of4-(2-carboxyethyl)-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 211(3),2-(2-chlorobenzyl)-4-[2,2-di(tert-butoxycarbonyl)ethyl]-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow powder (yield:99.1%).

¹H NMR(400 MHz, CDCl₃)δ: 2.31(3H, d, J=1.7 Hz), 2.81(2H, t, J=6.8 Hz),2.98(2H, t, J=6.8 Hz), 5.55(2H, s), 7.05(1H, dd, J=9.0, 9.0 Hz),7.16–7.25(3H, m), 7.41(1H, m), 7.50–7.57(2H, m), 7.59(1H, s).

4) Preparation of2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(3-hydroxypropyl)-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-(2-carboxyethyl)-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow oil (yield:77.2%).

¹H NMR(400 MHz, CDCl₃)δ: 1.88–1.95(2H, m), 2.32(3H, d, J=1.5 Hz),2.82(2H, t, J=7.1 Hz), 3.63(2H, t, J=6.8 Hz), 5.56(2H, s), 7.05(1H, dd,J=8.8, 8.8 Hz), 7.25–7.28(3H, m), 7.41(1H, m), 7.55–7.60(2H, m),7.56(1H, s).

5) Preparation of2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(3-hydroxypropyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 97.0%).

¹H NMR(400 MHz, CDCl₃)δ: 2.14–2.21(2H, m), 2.32(3H, d, J=1.7 Hz),2.81(2H, t, J=7.1 Hz), 3.02(3H, s), 4.30(2H, t, J=6.1 Hz), 5.54(2H, s),7.05(1H, dd, J=8.8, 8.8 Hz), 7.17–7.25(3H, m), 7.41(1H, m),7.53–7.62(2H, m), 7.58(1H, s).

6) Preparation of2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-[3-(4-methyl-1-piperazinyl)propyl]-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 75.9%).

¹H NMR(400 MHz, CDCl₃)δ: 1.84–1.95(2H, m), 2.32(3H, brs), 2.33(3H, s),2.45–2.58(8H,m), 2.70(2H, t, J=7.8 Hz), 3.26(2H, t, J=4.9 Hz), 5.54(2H,s), 7.05(1H, dd, J=8.8, 8.8 Hz), 7.15–7.23(3H, m), 7.40(1H, m), 7.51(1H,s), 7.53–7.59(2H, m). IR(Neat) cm⁻¹: 1655, 1608, 1447, 1239, 1014, 754.Mass m/z: 468 (M⁺), 470 (M⁺).

Example 227 Preparation of4-(3-aminopropyl)-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 24(1),2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-onewas reacted to yield a crude product. Without purification, the crudeproduct was reacted further in accordance with the procedure of Example24(2) to yield the title compound as a slightly-yellow crystallinepowder (yield: 43.9%).

Melting point: 80–85° C. ¹H NMR(400 MHz, CDCl₃)δ: 1.85–1.95 (2H, m),2.31 (3H, d, J=1.7 Hz), 2.74 (2H, t, J=7.8 Hz), 2.85(2H, t, J=6.8 Hz),5.54(2H, s), 7.04(1H, dd, J=8.8, 8.8 Hz), 7.15–7.24(3H, m), 7.40(1H, m),7.56(1H, s), 7.58–7.59(2H, m). IR(KBr) cm⁻¹: 3425, 1652, 1607, 1445,1238, 1039, 749. Mass m/z: 385(M⁺), 387(M⁺).

Example 228 Preparation of4-(3-aminopropyl)-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-(3-aminopropyl)-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a pale brown crystallinepowder (yield: 55.9%).

Melting point: 161–165° C. ¹H NMR(400 MHz, CD₃OD)δ: 1.98–2.06(2H, m),2.30(3H, brs), 2.77(2H, t, J=7.8 Hz), 3.00(2H, t, J=7.6 Hz), 5.56(2H,s), 7.10(1H, dd, J=9.0, 9.0 Hz), 7.19(1H, m), 7.24–7.33(2H, m), 7.45(1H,m), 7.67(1H, m), 7.72(1H, m), 7.94(1H, s). IR(KBr) cm⁻¹: 3435, 1644,1602, 1445, 1240, 1040, 748.

Example 229 Preparation of2-[2-(2-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one 1)Preparation of2-[2-(2-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and2-(2-chlorophenyl)ethanol methanesulfonate were reacted to yield thetitle compound as a pale yellow solid (yield: 59.8%).

¹H NMR(400 MHz, CDCl₃)δ: 2.32(3H, s), 3.33(2H, t, J=7.3 Hz), 3.99(3H,s), 4.58(2H, t, J=7.3 Hz), 7.05(1H, dd, J=8.8, 8.8 Hz), 7.14–7.27(3H,m), 7.34–7.44(3H, m), 8.19(1H, s).

2) Preparation of2-[2-(2-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

To a solution of2-[2-(2-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one(480 mg, 1.20 mmol) in THF/methanol (2 mL/1 mL), cerium(III) chloridehexahydrate (425 mg, 1.20 mmol) was added at −15° C., followed by theaddition of sodium borohydride (45 mg, 1.20 mmol). After stirred for 10minutes, a saturated aqueous solution of ammonium chloride was added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The extract was dried over anhydrous sodium sulfate, and wasconcentrated under reduced pressure. Further, the concentrate waspurified by column chromatography on silica gel [hexane/ethyl acetate(2/1)] to yield the title compound as a pale yellow syrupy substance(yield: 11.0%).

¹H NMR(400 MHz, CDCl₃)δ: 2.32(3H, d, J=2.0 Hz), 3.32(2H, t, J=7.2 Hz),4.54(2H, t, J=7.2 Hz), 4.69(2H, s), 7.05(1H, dd, J=9.2, 9.2 Hz),7.13–7.23(3H, m), 7.36(1H, m), 7.42–7.48(2H, m), 7.62(1H, d, J=1.0 Hz).

3) Preparation of2-[2-(2-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-[2-(2-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow syrup (yield:86.1%).

¹H NMR(400 MHz, CDCl₃)δ: 2.33(3H, d, J=1.8 Hz), 3.16(3H, s), 3.31(2H, t,J=7.2 Hz), 4.55(2H, t, J=7.2 Hz), 5.26(2H, d, J=1.4 Hz), 7.06(1H, dd,J=9.2, 9.2 Hz), 7.14–7.21(3H, m), 7.37(1H, m), 7.40–7.47(2H, m),7.72(1H, t, J=1.8 Hz).

4) Preparation of2-[2-(2-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-[2-(2-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow syrup (yield:61.2%).

¹H NMR(400 MHz, CDCl₃)δ: 2.33(6H, s), 2.46–2.67(8H, m), 3.31(2H, t,J=7.3 Hz), 3.57(2H, d, J=1.2 Hz), 4.53(2H, t, J=7.3 Hz), 7.05(1H, dd,J=9.3, 9.3 Hz), 7.13–7.24(3H, m), 7.36(1H, m), 7.42–7.47(2H, m),7.70(1H, s). IR(Neat) cm⁻¹: 1653, 1606, 1504, 1284, 1238, 1116.

Example 230 Preparation of2-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one 1)Preparation of4-carboxy-2-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and2-(4-chlorophenyl)ethanol methanesulfonate were reacted to yield a crudeproduct. Without purification, the crude product was reacted further inaccordance with the procedure of Example 1 (7) to yield the titlecompound as a pale yellow solid (yield: 56.3%).

¹H NMR(400 MHz, CDCl₃)δ: 2.36(3H, d, J=1.8 Hz), 3.20(2H, t, J=7.4 Hz),4.60(2H, t, J=7.4 Hz), 7.11(1H, dd, J=8.2, 8.2 Hz), 7.17(2H, d, J=8.4Hz), 7.22–7.31(2H, m), 7.49–7.55(2H, m), 8.59(1H, s).

2) Preparation of2-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow oil (yield:37.2%).

¹H NMR(400 MHz, CDCl₃)δ: 2.34(3H, d, J=2.0 Hz), 3.14(2H, t, J=7.4 Hz),4.47(2H, t, J=7.4 Hz), 4.70(2H, s), 7.07(1H, dd, J=9.2, 9.2 Hz),7.18(2H, d, J=8.4 Hz), 7.26(2H, d, J=8.4 Hz), 7.45–7.51(2H, m), 7.63(1H,t, J=1.2 Hz).

3) Preparation of2-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow solid (yield:34.0%).

¹H NMR(400 MHz, CDCl₃)δ: 2.35(3H, d, J=1.9 Hz), 3.11–3.17(5H, m),4.48(2H, t, J=7.3 Hz), 5.26(2H, d, J=1.5 Hz), 7.08(1H, dd, J=9.3, 9.3Hz), 7.17(2H, d, J=8.3 Hz), 7.24–7.29(2H, m), 7.44–7.53(2H, m), 7.73(1H,t, J=1.2 Hz).

4) Preparation of2-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 45.2%).

Melting point: 113–114° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.32(3H, s),2.35(3H, d, J=2.0 Hz), 2.45–2.66(8H, m), 3.13(2H, t, J=7.6 Hz), 3.57(2H,d, J=1.4 Hz), 4.46(2H, t, J=7.6 Hz), 7.08(1H, dd, J=8.5, 8.5 Hz),7.18(2H, d, J=8.3 Hz), 7.24–7.28(2H, m), 7.45–7.50(2H, m), 7.70(1H, t,J=1.4 Hz). IR(KBr) cm⁻¹: 1654, 1613, 1505, 1285, 1242, 1167, 1123.

Example 231 Preparation of2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one 1)Preparation of4-carboxy-2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and2,6-dichlorobenzyl bromide were reacted to yield a crude product.Without purification, the crude product was reacted further inaccordance with the procedure of Example 1(7) to yield the titlecompound as a pale yellow solid (90.3%).

¹H NMR(400 MHz, CDCl₃)δ: 2.28(3H, d, J=1.8 Hz), 5.81(2H, s), 7.03(1H,dd, J=8.8, 8.8 Hz), 7.31(1H, dd, J=8.8, 7.4 Hz), 7.39–7.49(4H, m),8.62(1H, s).

2) Preparation of2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow solid (yield:46.1%).

¹H NMR(400 MHz, CDCl₃)δ: 2.26(3H, d, J=1.7 Hz), 4.74(2H, s), 5.70(2H,s), 6.98(1H, dd, J=9.0, 9.0 Hz), 7.25(1H, dd, J=8.6, 7.3 Hz),7.32–7.45(4H, m), 7.66(1H, s).

3) Preparation of2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow solid (yield:78.9%).

¹H NMR(400 MHz, CDCl₃)δ: 2.27(3H, d, J=1.7 Hz), 3.17(3H, s), 5.31(2H, d,J=1.2 Hz), 5.69(2H, s), 6.99(1H, dd, J=8.8, 8.8 Hz), 726(1H, m),7.34–7.44(4H, m), 7.75(1H, t, J=1.4 Hz).

4) Preparation of2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 69.4%).

Melting point: 150–152° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.27(3H, d, J=1.8Hz), 2.33(3H, s), 2.45–2.67(8H, m), 3.62(2H, d, J=1.4 Hz), 5.69(2H, s),6.99(1H, dd, J=9.0, 9.0 Hz), 7.23(1H, dd, J=8.6, 7.4 Hz), 7.34–7.44(4H,m), 7.73(1H, s). IR(KBr) cm⁻¹: 1658, 1619, 1505, 1437, 1238, 1168.

Example 232 Preparation of2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one 1)Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand tert-butyl 1-piperazinecarboxylate were reacted to yield the titlecompound as a yellow oil (yield: 90.8%).

¹H NMR(400 MHz, CDCl₃)δ: 1.47(9H, s), 2.26(3H,s), 2.53(4H, t, J=4.9 Hz),3.50((4H, t, J=4.9 Hz), 3.61(2H, s), 5.69(2H, s), 6.98(1H, dd, J=8.8,8.8 Hz), 7.23(1H, dd, J=8.5, 7.3 Hz), 7.35–7.43(4H, m), 7.75(1H, s).

2) Preparation of2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 20,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless amorphous powder(yield: 84.6%).

¹H NMR(400 MHz, CDCl₃)δ: 2.27(3H, d, J=1.7 Hz), 2.51–2.60(4H, m),2.95(4H, t, J=4.6 Hz), 3.59(2H, d, J=1.2 Hz), 5.69(2H, s), 6.99(1H, dd,J=8.8, 8.8 Hz), 7.24(1H, m), 7.35–7.44(4H, m), 7.76(1H, s). IR(KBr)cm⁻¹: 1652, 1606, 1504, 1438, 1239, 1119.

Example 233 Preparation of4-aminomethyl-2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 24(1),2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield a crude product. Without purification, the crudeproduct was reacted further in accordance with the procedure of Example24(2) to yield the title compound as a yellow-brown crystalline powder(yield: 12.7%).

¹H NMR(400 MHz, CDCl₃)δ: 2.17(2H, brs), 2.25(3H, d, J=2.0 Hz), 3.94(2H,d, J=1.0 Hz), 5.69(2H, s), 6.97(1H, dd, J=9.0, 9.0 Hz), 7.24(1H, dd,J=8.5, 7.3 Hz), 7.34–7.45(4H, m), 7.70(1H, s). IR(KBr) cm⁻¹: 3362, 1643,1598, 1504, 1438, 1238, 1121.

Example 234 Preparation of2-[3-(2,6-dichlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one 1)Preparation of4-carboxy-2-[3-(2,6-dichlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and3-(2,6-dichlorophenyl)-1-propanol methanesulfonate were reacted to yielda crude product. Without purification, the crude product was reactedfurther in accordance with the procedure of Example 1 (7) to yield thetitle compound as a pale yellow solid (yield: 89.8%).

¹H NMR(400 MHz, CDCl₃)δ: 2.22–2.32(2H, m), 2.37(3H, d, J=2.0 Hz),3.03–3.08(2H, m), 4.50(2H, t, J=7.0 Hz), 7.06–7.17(2H, m), 7.25–7.29(2H,m), 7.64–7.72(2H, m), 8.63(1H, s), 14.12(1H, s).

2) Preparation of2-[3-(2,6-dichlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-[3-(2,6-dichlorophenyl)propyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow syrup (yield:31.9%).

¹H NMR(400 MHz, CDCl₃)δ: 2.14–2.24(2H, m), 2.35(3H, d, J=1.8 Hz),3.00–3.06(2H, m), 4.38(2H,t, J=7.0 Hz), 4.72(2H, d, J=1.5 Hz),7.01–7.12(2H, m), 7.23–7.28(2H, m), 7.57–7.70(3H, m).

3) Preparation of2-[3-(2,6-dichlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-[3-(2,6-dichlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow syrup (yield:25.8%).

¹H NMR(400 MHz, CDCl₃)δ: 2.14–2.23(2H, m), 2.36(3H, d, J=1.8 Hz),2.94–3.05(2H, m), 3.17(3H, s), 4.38(2H, t, J=7.0 Hz), 5.28(2H, d, J=11.4Hz), 7.02–7.12(2H, m), 7.23–7.27(2H, m), 7.57–7.69(2H, m), 7.76(1H, t,J=1.4 Hz).

4) Preparation of2-[3-(2,6-dichlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-[3-(2,6-dichlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow syrup (yield:49.7%).

¹H NMR(400 MHz, CDCl₃)δ: 2.13–2.22(2H, m), 2.33(3H, s), 2.36(3H, d,J=1.8 Hz), 2.45–2.67(8H, m), 2.99–3.05(2H, m), 3.58(2H, d, J=1.4 Hz),4.37(2H, t, J=7.0 Hz), 7.02–7.12(2H, m), 7.23–7.40(2H, m), 7.59(1H, m),7.65(1H, m), 7.73(1H, s). IR(Neat) cm⁻¹: 1653, 1607, 1504, 1436, 1238.

Example 235 Preparation of2-(3,4-difluorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one 1)Preparation of4-carboxy-2-(3,4-difluorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and3,4-difluorobenzyl chloride were reacted to yield a crude product.Without purification, the crude product was reacted further inaccordance with the procedure of Example 1(7) to yield the titlecompound as a pale yellow solid (66.7%).

¹H NMR(400 MHz, CDCl₃)δ: 2.36(3H, d, J=2.0 Hz), 5.43(2H, s),7.09–7.20(2H, m), 7.25(1H, m), 7.34(1H, m), 7.60–7.68(2H, m), 8.61(1H,s).

2) Preparation of2-(3,4-difluorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-(3,4-difluorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow solid (yield:40.8%).

¹H NMR(400 MHz, CDCl₃)δ: 2.33(3H, d, J=2.0 Hz), 4.69(2H, d, J=1.2 Hz),5.31(2H, s), 6.98–7.17(2H, m), 7.21(1H, m), 7.30(1H, m), 7.53–7.62(2H,m), 7.67(1H, s).

3) Preparation of2-(3,4-difluorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-(3,4-difluorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow solid (yield:58.1%).

¹H NMR(400 MHz, CDCl₃)δ: 2.34(3H, d, J=1.7 Hz), 3.13(3H, s), 5.24(2H, d,J=1.2 Hz), 5.31(2H, s), 7.05–7.15(2H, m), 7.22(1H, m), 7.30(1H, m),7.54–7.62(2H, m), 7.75(1H, s).

4) Preparation of2-(3,4-difluorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-(3,4-difluorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow amorphouspowder (yield: 70.6%).

¹H NMR(400 MHz, CDCl₃)δ: 2.32(3H, s), 2.36(3H, d, J=1.5 Hz),2.45–2.70(8H, m), 3.56(2H, d, J=1.3 Hz), 5.32(2H, s), 7.07–7.15(2H, m),7.23(1H, m), 7.31(1H, m), 7.57(1H, m), 7.63(1H, m), 7.75(1H, s).

Example 236 Preparation of2-(3,4-difluorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-(3,4-difluorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 47.9%).

Melting point: 220–225° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 2.31(3H, s),2.81(3H, s), 3.52(2H, brs), 3.60–4.25(8H, m), 5.35(2H, s), 7.25(1H, m),7.30(1H, dd, J=9.3, 9.3 Hz), 7.38–7.50(2H, m), 7.76(1H, m), 7.84(1H, d,J=7.3 Hz), 8.27(1H, m). IR(KBr) cm⁻¹: 3438, 3011, 2446, 1652, 1605,1519.

Example 237 Preparation of4-aminomethyl-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

Following the procedure of Example 24(1),2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield a crude product. Without purification, the crudeproduct was reacted further in accordance with the procedure of Example24 (2) to yield the title compound as a pale yellow crystalline powder(26.7%).

Melting point: 97.6–102.2° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.31(3H, d, J=1.7Hz), 3.48(2H, s), 5.55(2H, s), 7.05(1H, dd, J=8.8, 8.8 Hz),7.15–7.25(3H, m), 7.41(1H, m), 7.58(1H, m), 7.62(1H, dd, J=7.3, 1.7 Hz),7.76(1H, s). IR(KBr) cm⁻¹: 3404, 1648, 1600, 1505, 1239. Mass m/z:357(M⁺), 359(M⁺).

Example 238 Preparation of4-aminomethyl-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,4-aminomethyl-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow needles (yield:68.9%).

Melting point: 201.9–206.4° C. ¹H NMR(400 MHz, CD₃OD)δ: 2.31(3H, d,J=1.7 Hz), 4.17(2H, s), 5.57(2H, s), 7.12(1H, dd, J=8.8, 8.8 Hz),7.25–7.35(3H, m), 7.46(1H, m), 7.67 (1H, m), 7.73(1H, d, J=6.9 Hz),8.15(1H, s). IR(KBr) cm⁻¹: 3430, 2929, 1652, 1604, 1507, 1476, 1445,1241. Mass m/z: 357(M⁺), 359(M⁺).

Example 239 Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-[3-(4-methyl-1-piperazinyl)propyl]-2H-pyridazin-3-one 1)Preparation of4-bromomethyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 211(1),2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow needles (yield:28.8%).

Melting point: 120–125° C. ¹H NMR(400 MHz, CDCl₃)δ: 3.95(3H, s),4.46(2H, s), 5.37(2H, s), 6.95–7.06(4H, m), 7.46–7.52(2H, m), 7.60(1H,m), 7.77(1H, s).

2) Preparation of4-[2,2-di(tert-butoxycarbonyl)ethyl]-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 211(2),4-bromomethyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 75.1%).

¹H NMR(400 MHz, CDCl₃)δ: 1.38(18H, s), 3.10(2H, d, J=7.6 Hz), 3.84(1H,t, J=7.6 Hz), 3.94(3H, s), 5.34(2H, s), 6.98–7.04(3H,m), 7.41–7.50(4H,m), 7.56(1H, m).

3) Preparation of4-(2-carboxyethyl)-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 211(3),4-[2,2-di-(tert-butoxycarbonyl)ethyl]-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a slightly-yellow powder(yield: 78.8%).

¹H NMR(400 MHz, CDCl₃)δ: 2.78(2H, t, J=7.1 Hz), 2.95(2H, t, J=7.1 Hz),3.94(3H, s), 534(2H, s), 6.99–7.05(3H,m), 7.44–7.51(3H, m), 7.52(1H, s),7.58(1H, dd, J=12.4, 2.2 Hz).

4) Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(3-hydroxypropyl)-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-(2-carboxyethyl)-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow powder (yield:98.0%).

¹H NMR(400 MHz, CDCl₃)δ: 1.85–1.97(2H, m), 2.78(2H, t, J=7.1 Hz),3.61(2H, t, J=5.9 Hz), 3.95(3H, s), 5.36(2H, s), 6.99–7.05(3H, m),7.45–7.50(4H, m), 7.58(1H, dd, J=12.4, 2.2 Hz).

5) Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(3-hydroxypropyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a pale brown crystallinepowder (yield: 97.0%).

Melting point: 101–103° C. ¹H NMR(400 MHz, CDCl₃)δ: 2.11–2.18(2H, m),2.78(2H, t, J=7.3 Hz), 3.02(3H, s), 3.94(3H, s), 4.28(2H, t, J=6.1 Hz),5.34(2H, s), 7.00–7.04(3H, m), 7.47–7.50(3H, m), 7.52(1H, s), 7.61(1H,dd, J=12.4, 2.2 Hz).

6) Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-[3-(4-methyl-1-piperazinyl)propyl]-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a pale brown powder (yield:29.8%).

Melting point: 108–109° C. ¹H NMR(400 MHz, CDCl₃)δ: 1.84–1.90(2H, m),2.32(3H, s), 2.45(2H, t, J=7.1 Hz), 2.48–2.60(8H, m), 2.66(2H, t, J=7.3Hz), 3.94(3H, s), 5.33(2H, s), 6.98–7.05(3H, m), 7.44(1H, s),7.45–7.51(3H, m), 7.58(1H, dd, J=12.4, 2.2 Hz). IR(KBr) cm⁻¹: 1645,1601, 1438, 1220, 1016, 807. Mass m/z: 468(M⁺).

Example 240 Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one 1)Preparation of4-[3-(4-tert-butoxycarbonyl-1-piperazinyl)propyl]-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-oneand tert-butyl 1-piperazinecarboxylate were reacted to yield the titlecompound as a brown oil (yield: 37.4%).

¹H NMR(400 MHz, CDCl₃)δ: 1.46(9H, s), 1.80–2.00(2H, m), 2.30–2.60(8H,m), 2.67(2H, t, J=7.1 Hz), 3.40–3.52(2H, m), 3.94(3H, s), 5.33(2H, s),6.99–7.05(3H, m), 7.45–7.51(4H, m), 7.59(1H, dd, J=12.4, 2.0 Hz).

2) Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one

Following the procedure of Example 20,4-[3-(4-tert-butoxycarbonyl-1-piperazinyl)propyl]-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a brown oil (yield: 100%).

¹H NMR(400 MHz, CDCl₃)δ: 1.80–1.91(2H, m), 2.37–2.51(6H, m), 2.66(2H, t,J=7.6 Hz), 2.89–2.95(4H, m), 3.94(3H, s), 5.34(2H, s), 6.98–7.05(3H, m),7.44(1H, s), 7.45–7.51(3H, m), 7.58(1H, dd, J=11.5, 2.2 Hz). IR(Neat)cm⁻¹: 1651, 1608, 1438, 1222, 1025, 757. Mass m/z: 454(M⁺).

Example 241 Preparation of2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one 1)Preparation of4-carboxy-2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and3-(2-chlorophenyl)-1-propanol methanesulfonate were reacted to yield acrude product. Without purification, the crude product was reactedfurther in accordance with the procedure of Example 1 (7) to yield thetitle compound as a pale yellow solid (yield: 56.0%).

¹H NMR(400 MHz, CDCl₃)δ: 2.25–2.38(2H, m), 2.86(2H, t, J=7.8 Hz),3.95(3H, s), 4.42(2H, t, J=7.8 Hz), 7.04(1H, dd, J=8.5, 8.5 Hz),7.09–7.19(2H, m), 7.23(1H, m), 7.30(1H, m), 7.54(1H, m), 7.65(1H, dd,J=12.2, 2.4 Hz), 8.56(1H, s).

2) Preparation of2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow solid (yield:32.5%).

¹H NMR(400 MHz, CDCl₃)δ: 2.17–2.28(2H, m), 2.84(2H, t, J=7.6 Hz),3.94(3H, s), 4.31(2H, t, J=7.0 Hz), 4.71(2H, d, J=0.8 Hz), 7.01(1H, dd,J=8.6, 8.6 Hz), 7.13(1H, ddd, J=7.6, 7.6, 2.0 Hz), 7.18(1H, ddd, J=7.4,7.4, 1.4 Hz), 7.26(1H, dd, J=7.4, 1.7 Hz), 7.32(1H, dd, J=7.6, 1.4 Hz),7.51(1H, ddd, J=8.6, 2.1, 1.2 Hz), 7.61(1H, dd, J=12.3, 2.2 Hz),7.66(1H, s).

3) Preparation of2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow solid (yield:79.3%).

¹H NMR(400 MHz, CDCl₃)δ: 2.18–2.28(2H, m), 2.85(2H, t, J=7.6 Hz),3.17(3H, s), 3.95(3H, s), 4.32(2H, t, J=7.3 Hz), 5.27(2H, d, J=1.2 Hz),7.03(1H, dd, J=8.5, 8.5 Hz), 7.13(1H, ddd, J=7.6, 7.6, 2.0 Hz), 7.18(1H,ddd, J=7.3, 7.3, 1.4 Hz), 7.26(1H, m), 7.32(1H, dd, J=7.6, 1.4 Hz),7.50(1H, ddd, J=8.6, 2.2, 1.2 Hz), 7.62(1H, dd, J=12.2, 2.2 Hz),7.74(1H, t, J=1.2 Hz).

4) Preparation of2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow syrup (yield:76.7%).

¹H NMR(400 MHz, CDCl₃)δ: 2.17–2.26(2H, m), 2.33(3H, s), 2.46–2.68(8H,m), 2.84(2H, t, J=7.6 Hz), 3.57(2H, d, J=1.5 Hz), 3.95(3H, s), 4.31(2H,t, J=7.1 Hz), 7.04(1H, dd, J=8.6, 8.6 Hz), 7.12(1H, ddd, J=7.6, 7.6, 1.7Hz), 7.18(1H, ddd, J=7.3, 7.3, 1.4 Hz), 7.27(1H, m), 7.32(1H, dd, J=7.8,1.5 Hz), 7.53(1H, ddd, J=8.6, 2.2, 1.0 Hz), 7.61(1H, dd, J=12.4, 2.2Hz), 7.73(1H, s). IR(Neat) cm⁻¹: 1652, 1608, 1521, 1437, 1290.

Example 242 Preparation of2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one 1)Preparation of4-carboxy-2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 1(6),6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and3-(4-chlorophenyl)-1-propanol methanesulfonate were reacted to yield acrude product. Without purification, the crude product was reactedfurther in accordance with the procedure of Example 1 (7) to yield thetitle compound as a pale yellow solid (yield: 56.1%).

¹H NMR(400 MHz, CDCl₃)δ: 2.20–2.29(2H, m), 2.72(2H, t, J=7.3 Hz),3.95(3H, s), 4.37(2H, t, J=7.3 Hz), 7.05(1H, dd, J=8.5, 8.5 Hz),7.10(2H, d, J=8.5 Hz), 7.22(2H, d, J=8.5 Hz), 7.53(1H, m), 7.63(1H, dd,J=12.2, 2.2 Hz), 8.56(1H, s).

2) Preparation of2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(8),4-carboxy-2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow solid (yield:32.5%).

¹H NMR(400 MHz, CDCl₃)δ: 2.14–2.24(2H, m), 2.69(2H, t, J=7.6 Hz),3.33(1H, m), 3.94(3H, s), 4.26(2H, t, J=7.2 Hz), 4.69(2H, d, J=1.4 Hz),7.01(1H, dd, J=8.4, 8.4 Hz), 7.13(2H, d, J=8.2 Hz), 7.22(2H, d, J=8.2Hz), 7.49(1H, ddd, J=8.4, 2.0, 1.2 Hz), 7.60(1H, dd, J=12.5, 2.1 Hz),7.65(1H, s).

3) Preparation of2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

Following the procedure of Example 1(9),2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow solid (yield:79.3%).

¹H NMR(400 MHz, CDCl₃)δ: 2.15–2.24(2H, m), 2.70(2H, t, J=7.3 Hz),3.17(3H, s), 3.95(3H, s), 4.27(2H, t, J=6.8 Hz), 5.25(2H, d, J=1.2 Hz),7.03(1H, dd, J=8.6, 8.6 Hz), 7.13(2H, d, J=8.5 Hz), 7.23(2H, d, J=8.5Hz), 7.49(1H, ddd, J=8.6, 2.2, 1.2 Hz), 7.61(1H, dd, J=12.2, 2.2 Hz),7.72(1H, t, J=1.2 Hz).

4) Preparation of2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

Following the procedure of Example 1(10),2-(3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow syrup (yield:76.9%).

¹H NMR(400 MHz, CDCl₃)δ: 2.15–2.24(2H, m), 2.33(3H, s), 2.47–2.66(8H,m), 2.70(2H, t, J=7.6 Hz), 3.55(2H, d, J=1.4 Hz), 3.95(3H, s), 4.27(2H,t, J=7.1 Hz), 7.04(1H, dd, J=8.8, 8.8 Hz), 7.13(2H, d, J=8.5 Hz),7.21(2H, d, J=8.5 Hz), 7.49(1H, m), 7.60(1H, dd, J=12.4, 2.2 Hz),7.70(1H, s). IR(Neat) cm⁻¹: 1652, 1608, 1521, 1437, 1282.

Example 243 Preparation of4-aminomethyl-2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 24(1),2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield a crude product. Without purification, the crudeproduct was reacted further in accordance with the procedure of Example24(2) to yield the title compound as a pale yellow syrup (yield: 48.2%).

¹H NMR(400 MHz, CDCl₃)δ: 2.17–2.27(2H, m), 2.85(2H, t, J=7.4 Hz),3.89(2H, d, J=1.2 Hz), 3.94(3H, s), 4.32(2H, t, J=7.0 Hz), 7.02(1H, dd,J=8.6, 8.6 Hz), 7.13(1H, ddd, J=7.6, 7.6, 2.0 Hz), 7.18(1H, ddd, J=7.4,7.4, 1.6 Hz), 7.27(1H, m), 7.32(1H, dd, J=7.6, 1.4 Hz), 7.52(1H, m),7.62(1H, dd, J=12.5, 2.2 Hz), 7.67(1H, s). IR(Neat) cm⁻¹: 1652, 1604,1522, 1438, 1275.

Example 244 Preparation of4-aminomethyl-2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of Example 24(1),2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield a crude product. Without purification, the crudeproduct was reacted further in accordance with the procedure of Example24(2) to yield the title compound as a pale yellow solid (yield: 48.2%).

¹H NMR(400 MHz, CDCl₃)δ: 2.14–2.26(2H, m), 2.70(2H, t, J=7.4 Hz),3.87(2H, s), 3.95(3H, s), 4.27(2H, t, J=7.2 Hz), 7.02(1H, dd, J=8.6, 8.6Hz), 7.14(2H, d, J=8.4 Hz), 7.22(2H, d, J=8.4 Hz), 7.51(1H, d, J=8.0Hz), 7.61(1H, dd, J=12.5, 2.2 Hz), 7.65(1H, s). IR(KBr) cm⁻¹: 1652,1604, 1522, 1438, 1275.

Example 245 Preparation of2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 91.6%).

Melting point: 235–239° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ: 2.75(3H,s), 3.16–3.42(8H, m), 3.63(2H, s), 3.90(3H, s), 5.31(2H, s),7.19–7.40(4H, m), 7.60–7.67(2H, m), 7.87(1H, s). IR(KBr) cm⁻¹: 3439,1652, 1605, 1519, 1441, 1290, 1139.

Example 246 Preparation of2-(3,4-difluorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onehydrochloride

Following the procedure of Example 4,2-(3,4-difluorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 91.1%).

Melting point: 216–218° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 2.77(6H, s),3.91(3H, s), 4.24(2H, s), 5.35(2H, s), 7.21–7.44(4H, m), 7.66–7.74(2H,m), 8.45(1H, s). IR(KBr) cm⁻¹: 3435, 1647, 1606, 1519, 1438, 1284.

Example 247 Preparation of2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 50.0%).

Melting point: 244–245° C. ¹H NMR(400 MHz, DMSO-d₆)δ: 2.05–2.15(2H, m),2.32(3H, s), 2.68(2H, t, J=7.8 Hz), 2.81(3H, s), 3.20–3.60(10H, m),4.18(2H, t, J=7.8 Hz), 7.27(2H, d, J=8.6 Hz), 7.29–7.39(3H, m), 7.75(1H,m), 7.80(1H, m), 8.37(1H, brs). IR(KBr) cm⁻¹: 1650, 1607, 1493, 1241,1158, 1016, 942, 827.

Example 248 Preparation of2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 85.2%).

Melting point: 248–250° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ: 2.76(3H,s), 2.98–3.18(4H, m), 3.25–3.39(4H, m), 3.82(2H, s), 3.90(3H, s),4.92(2H, d, J=6.4 Hz), 6.46(1H, dt, J=15.6, 6.4 Hz), 6.65(1H, d, J=15.6Hz), 7.25(1H, dd, J=8.5, 8.5 Hz), 7.33(2H, d, J=8.5 Hz), 7.44(2H, d,J=8.5 Hz), 7.65–7.73(2H, m), 8.07(1H, s). IR(KBr) cm⁻¹: 2936, 1652,1607, 1523, 1439, 1286.

Example 249 Preparation of2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-[4-(2-hydroxyethyl)-1-piperazinyl]methyl-2H-pyridazin-3-onedihydrochloride

Following the procedure of Example 4,2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-[4-(2-hydroxyethyl)-1-piperazinyl]methyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 82.6%).

Melting point: 220–228° C. (dec.) ¹H NMR(400 MHz, DMSO-d₆)δ:2.96–3.08(4H, m), 3.17(2H, t, J=5.4 Hz), 3.28–3.44(4H, m), 3.75(2H, s),3.79(2H, t, J=5.1 Hz), 3.90(3H, s), 4.92(2H, dd, J=6.4, 1.2 Hz),6.46(1H, dt, J=16.1, 6.4 Hz), 6.65(1H, d, J=16.1 Hz), 7.25(1H, dd,J=8.5, 8.5 Hz), 7.33(2H, d, J=8.5 Hz), 7.44(2H, d, J=8.5 Hz),7.65–7.72(2H, m), 8.00(1H, s). IR(KBr) cm⁻¹: 2937, 1656, 1611, 1525,1438, 1285.

Experiment 1

Inhibitory Activity Against Interleukin-1β Production

HL-60 cells were cultured for 4 days until confluence on RPMI 1640medium with 10% fetal bovine serum (FBS) added thereto. The medium wascentrifuged. The supernatant was discarded, and the cells were thensuspended at 1×10⁶ cells/mL on RPMI 1640 medium with 3% FBS, andlipopolysaccharide was added to give a final concentration of 10 μg/mL.The culture was inoculated at 1 mL/well to a 24-well plate. A samplecompound was added at 1 μL/well, followed by culturing for 3 days. Threedays later, the amount of interleukin-1β in each culture was determinedby ELISA. Each IC₅₀ value was determined by a comparison in yield with acontrol to which no test sample was added. Results on somerepresentative compounds are shown in Tables 1 and 2.

TABLE 1 (1)

CyprCH₂ Cyclopropylmethyl IL-1β production Example inhibiting activityNo. X Y Z n R¹ R²(R³)N— Salt IC50 (μM) 8 Me F H 1 iso-Bu Me₂N— HCl 3.4514 MeO F H 1 CyprCH₂ Me₂N— HCl 3.61 18 MeO F H 1 CyprCH₂

2HCl 5.40 21 MeO F H 1 CyprCH₂

2HCl 1.01 23 MeO F H 1 CyprCH₂ (HOCH₂CH₂)₂N— HCl 0.33 25 MeO F H 1CyprCH₂ H₂N— HCl 2.74 45 Me H H 1 iso-Bu Me₂N— HCl 6.21 47 Me H H 1iso-Bu Et₂N— HCl 5.20 49 Me F H 1 iso-Bu (HOCH₂CH₂)₂N— HCl 3.53 83 F MeH 1 iso-Bu

2HCl 0.27 89 F Me H 1 iso-Bu Me₂N— HCl 5.50 108 F F H 1 iso-Bu(HOCH₂CH₂)₂N— HCl 3.44 143 F Me H 1

2HCl 8.55 149 MeS H H 1 CyprCH₂

2HCl 1.63 153 MeS H H 1 CyprCH₂ Me₂N— HCl 0.58 161 MeS H H 1 iso-BuMe₂N— HCl 2.78 163 MeS H H 1 iso-Bu

HCl 2.78 189 MeO F H 1

free 0.87 192 MeO F H 1

free 0.64 213 MeO F H 3 CyprCH₂

free 0.24 216 MeO F H 3 CyprCH₂ H₂N— free 1.14

TABLE 2 (1)

IL-1β production Example inhibiting activity No. X Y Z n R¹ A IC50 (μM)207 MeO F H 1

2.7 208 MeO F H 1

Me₂N— 6.1 209 MeO F H 1

2.8 210 MeO F H 1

3.1 218 F Me H 1

6.8 222 F Me H 1

5.8 227 F Me H 3

H₂N— 5.2 230 F Me H 1

4.0 231 F Me H 1

5.7 241 MeO F H 1

6.4 242 MeO F H 1

7.7Experiment 2 (Water Solubility Test)Testing Method

Each sample compound was weighed in the amount shown in Table 3, towhich purified water was added in 0.05 mL aliquots. The solubility (%)of the compound was determined based on the amount of water required forits dissolution.

Results

As is shown in Table 3, the compounds of the present invention showedwater solubility significantly improved over the comparative compounds.

TABLE 3 Weighed amount Amount of added Example No. (mg) water (mL)Solubility (%) 14 2.048 0.25 0.8 18 1.048 0.1 1 21 10.47 0.05 >20 2310.82 0.1 10 25 1.025 0.25 0.4 45 10.37 0.25 4 47 10.47 0.05 >20 8910.57 0.05 >20 108 9.75 0.045 >20 143 5.023 0.05 10 149 3.09 0.03 >10153 2.95 0.6 0.5 188 2.008 2.5 0.08 193 5.032 0.1 5 195 5.072 2.2 0.2206 2.042 3.5 0.06 214 5.061 0.05 10 217 5.061 0.05 10 245 5.020 0.05 10246 4.992 0.2 2 247 4.999 0.05 10 248 2.002 3.5 0.06 249 2.017 7.0 0.03Comparative 0.677 100 <0.001 Compound 1 (insoluble) Comparative 0.742100 <0.001 Compound 2 (insoluble) Comparative 0.740 100 <0.001 Compound3 (insoluble) Comparative 0.95 100 <0.001 Compound 4 (insoluble)

Comp. comp'd 1

Comp. comp'd 2

Comp. comp'd 3

Comp. comp'd 4Experiment 3 (Oral Absorbability Test on Rats)

The compound of Example 83 and the comparative compound 3 were suspendedat 2 mg/mL with a 0.5% MC solution in mortars, respectively, and wereorally administered to male SD rats at 10 mg/5 mL/kg. Upon elapsed timeof 0.25, 0.5, 1, 2, 4, 6 and 8 hours after the administration, bloodsamples were collected and then centrifuged to provide plasma samples.The plasma levels of the respective compounds were determined by HPLC.As is shown in FIG. 1, no substantial absorption was observed on thecomparative compound 3, but good absorption was observed on the compoundof Example 83 equipped with increased water solubility. The compound ofExample 83 is, therefore, useful as an orally dosable medicine.

Experiment 4 (Oral Absorbability Test on Rats and/or Mice)

In a similar manner as in Experiment 3, test compounds of Examples 23,25, 143, 193, 245, 246, 247, 248 and 249 were orally administered tomice and/or rats to test their oral absorbability. As is shown in FIGS.2 to 6, good absorbability was observed on all the test compounds ofExamples 23, 25, 143, 193, 245, 246, 247, 248 and 249 so that they areuseful as orally dosable medicines.

1. A phenylpyridazine derivative represented by the formula (1):

wherein: R¹ is optionally substituted or unsubstituted C₁–C₁₂ alkyl, orsubstituted or unsubstituted C₂–C₁₂ alkenyl; wherein the alkyl can belinear, branched, cyclic or a structure containing a cylic structuretherein, wherein, if substituted, the substituent on the alkyl oralkenyl represented by R¹ is independently a substituted orunsubstituted C₆–C₁₄ aryl or a 5- or 6-membered heteroaryl having 1 to 3nitrogen atoms; and said aryl or heteroaryl, wherein if substituted, thearyl or heteroaryl are substituted with 1 to 3 substituents selectedfrom the group consisting of halogen, C₁–C₁₂ alkyl, C₁–C₁₂ alkoxy, andcombinations thereof; R² and R³ each independently represents hydrogenor C₁–C₁₂ alkyl, hydroxy C₁–C₁₂ alkyl, dihydroxy C₁–C₁₂alkyl orC₃–C₁₂alkynyl, or R² and R³ are fused together with the adjacentnitrogen atom to form a substituted or unsubstituted,nitrogen-containing, saturated 5- to 7-membered heterocyclic group;wherein, if substituted, the 5- to 7-membered heterocyclic group issubstituted with at least one of a halogen atom, C₁–C₁₂ alkyl, C₁–C₁₂alkoxycarbonyl or phenyl-C₁–C₇ alkyl, X, Y and Z each independentlyrepresents hydrogen, halogen, substituted or unsubstituted C₁–C₁₂ alkyl,C₁–C₁₂ alkoxy, C₁–C₁₂ alkylthio, C₁–C₁₂ alkylsulfinyl,C₁–C₁₂alkylsulfonyl, or C₆–C₁₄ aryl; wherein the C₁–C₁₂ alkyl isoptionally substituted with at least one of a halogen atom or C₁–C₁₂alkoxy, the aryl is optionally substituted with at least one of ahalogen, C₁–C₁₂ alkyl, or C₁–C₁₂ alkoxy; and n stands for a number offrom 1 to 5; with the proviso that R² and R³ are not hydrogens or thesame C₁–C₃ alkyl groups at the same time when R¹ is a benzyl group or aC₁–C₃ alkyl group; or a salt thereof.
 2. The compound of claim 1,wherein R¹ is a group selected from halogenobenzyl, dihalogenobenzyl,(halogenophenyl)ethyl, (dihalogenophenyl)ethyl, (halogenophenyl)propylor (dihalogenophenyl)propyl; R²(R³)N— is a group selected from amino,dimethylamino, piperazinyl or N-methylpiperazinyl; X is halogen ormethoxy; Y is methyl or halogen; Z is hydrogen; and n stands for 1 or 3.3. The compound of claim 1, wherein R¹ is a group selected fromchlorobenzyl, dichlorobenzyl, fluorobenzyl, difluorobenzyl,(chlorophenyl)ethyl, (dichlorophenyl)ethyl, (chlrorophenyl)propyl or(dichlorophenyl)propyl; R²(R³)N— is a group selected from amino,dimethylamino, piperazinyl or N-methylpiperazinyl; X is halogen ormethoxy; Y is methyl or halogen; Z is hydrogen; and n stands for 1 or 3.4. A pharmaceutical composition comprising the compound of claim 1 or asalt thereof and a pharmacologically acceptable carrier.
 5. A method oftreating osteoporosis or ichorrhemia in an individual comprising,administering the compound of claim 1 or a salt thereof in an amountsufficient to treat osteoporosis or ichorrhemia in the individual.
 6. Amethod of treating rheumatism, arthritis or inflammatory colitis in anindividual comprising, administering the compound of claim 1 or a saltthereof in an amount sufficient to treat osteoporosis or ichorrhemia inthe individual.
 7. A phenylpyridazine derivative represented by theformula (1):

wherein: R¹ is optionally substituted or unsubstituted C₁–C₇ alkyl, orsubstituted or unsubstituted C₂–C₇ alkenyl; wherein the alkyl can belinear, branched, cyclic or a structure containing a cylic structuretherein, wherein, if substituted, the substituent on the alkyl oralkenyl represented by R¹ is phenyl, which is optionally substitutedwith 1 to 3 substituents selected from the group consisting of halogen,C₁–C₇ alkyl, C₁–C₇ alkoxy, and combinations thereof; R² and R³ eachindependently represents hydrogen or C₁–C₇ alkyl or R² and R³ are fusedtogether with the adjacent nitrogen atom to form a piperazinyl, whereinthe piperazinyl is optionally substituted with one or more of an alkylor a hydroxyl-C₁–C₇-alkyl; X, Y and Z each independently representshydrogen, halogen, C₁–C₇ alkyl, or C₁–C₇ alkoxy; and n stands for anumber of from 1 to 5; with the proviso that R² and R³ are not hydrogensor the same C₁–C₃ alkyl groups at the same time when R¹ is a benzylgroup or a C₁–C₃ alkyl group; or a salt thereof.
 8. A pharmaceuticalcomposition comprising the compound of claim 7 or a salt thereof and apharmacologically acceptable carrier.
 9. A method of treatingosteoporosis, or ichorrhemia in an individual comprising, administeringthe compound of claim 7 or a salt thereof in an amount sufficient totreat osteoporosis or ichorrhemia in the individual.
 10. A method oftreating rheumatism, arthritis or inflammatory colitis in an individualcomprising, administering the compound of claim 7 or a salt thereof inan amount sufficient to treat osteoporosis or ichorrhemia in theindividual.